Pyrimidine derivatives

ABSTRACT

Compounds of the formula ##STR1## wherein R 1  is halogen, C 1-4  -alkyl, halo-(C 1-4  -alkyl) or C 2-4  -alkanoyl, 
     R 2  is hydrogen, hydroxy, C 1-4  alkoxy, C 1-4  -alkylthio or phenyl-(C 1-4  -alkoxy) or , when X is O, also acyloxy, 
     R 3  is hydrogen or C 1-4  -alkyl, 
     R 4  is a carbocyclic group or a heterocyclic group, 
     R 5  is hydrogen or fluorine, 
     m stands for zero, 1 or 2, 
     X is O or NH and Y is a direct bond, --CH═CH--, --C.tbd.C-- or a group of the formula of 
     
         --(Z).sub.n --A--                                          (a) 
    
     in which A is a C 1-8  alkylene group which is optionally substituted by one or two phenyl groups, 
     Z is O, S, SO or SO 2  and n stands for zero or 1, with the proviso that R 1  is different from iodine, when R 2  is hydroxy or benzoyloxy, R 3  is hydrogen, 
     R 4  is unsubstituted phenyl, R 5  is hydrogen, m stands for zero, X is O, and Y is a direct bond, and tautomers thereof, which possess antiviral activity and can therefore be used in the form of medicaments for the control and prevention of viral infections are described. The compounds of formula I can be prepared according to known methods.

BRIEF DESCRIPTION OF THE INVENTION

The invention relates to pyrimidine derivatives, a process for theirpreparation and medicaments containing said derivatives.

The pyrimidine derivatives provided by the invention are compounds ofthe formula ##STR2## wherein

R¹ is halogen, C₁₋₄ -alkyl, halo-(C₁₋₄ -alkyl) or C₂₋₄ -alkanoyl,

R² is hydrogen, hydroxy, C₁₋₄ -alkoxy, C₁₋₄ -alkylthio or phenyl-(C₁₋₄-alkoxy) or, when X is O, also acyloxy,

R³ is hydrogen or C₁₋₄ -alkyl,

R⁴ is a carbocyclic group or a heterocyclic group,

R⁵ is hydrogen or fluorine,

m stands for zero, 1 or 2,

X is O or NH and Y is a direct bond, --CH═CH--, --C.tbd.C-- or a groupof the formula of

    --(Z).sub.n --A--                                          (a)

in which A is a C₁₋₈ -alkylene group which is optionally substituted byone or two phenyl groups.

Z is O, S, So or SO₂ and n stands for zero or 1, with the proviso thatR¹ is different from iodine, when R² is hydroxy or benzoyloxy, R³ ishydrogen, R⁴ is unsubstituted phenyl, R⁵ is hydrogen, m stands for zero,X is O, and Y is a direct bond, and tautomers thereof.

The compounds of formula I and their tautomers possess antiviralactivity and can be used in the control, treatment or prevention ofviral infection, for example, herpes simplex viral infections.

DETAILED DESCRIPTION OF THE INVENTION

The pyrimidine derivatives provided by the present invention arecompounds of the formula ##STR3## wherein

R¹ is halogen, C₁₋₄ -alkyl, halo-(C₁₋₄ -alkyl) or C₂₋₄ -alkanoyl,

R² is hydrogen, hydroxy, C₁₋₄ -alkoxy, C₁₋₄ -alkylthio or phenyl-(C₁₋₄-alkoxy) or, when X is O, also acyloxy,

R³ is hydrogen or C₁₋₄ -alkyl,

R⁴ is a carbocyclic group or a heterocyclic group,

R⁵ is hydrogen or fluorine,

m stands for zero, 1 or 2,

X is O or NH and Y is a direct bond, --CH═CH--, --C.tbd.C-- or a groupof the formula of

    --(Z).sub.n --A--                                          (a)

in which A is a C₁₋₈ -alkylene group which is optionally substituted byone or two phenyl groups,

Z is O, S, SO or SO₂ and n stands for zero or 1, with the proviso thatR¹ is different from iodine, when R² is hydroxy or benzoyloxy, R³ ishydrogen, R⁴ is unsubstituted phenyl, R⁵ is hydrogen, m stands for zero,X is O, and Y is a direct bond, and tautomers thereof.

As used therein, the term "C₁₋₄ -alkyl" taken alone or in combinationdenotes a straight- or branched-chain alkyl group, such as methyl,ethyl, propyl, isopropyl or t-butyl. Examples of "halo-(C_(1:4) -alkyl)"groups are trifluoromethyl and 2-chloroethyl. Examples of "C₁₋₄-alkylthio" groups are methylthio and ethylthio. Examples of "C₁₋₄-alkoxy" groups are methoxy and ethoxy. Examples of "C₂₋₄ -alkanoyl"groups are acetyl, propionyl and butyryl. Benzyloxy can be mentioned asan example of a phenyl-(C₁₋₄ -alkoxy) group. The acyloxy group can bederived from an aliphatic, cycloaliphatic, araliphatic or aromaticcarboxylic acid, examples of such acids are formic acid, acetic acid,propionic acid, butyric acid, t-butylacetic acid, palmitic acid,cyclopentylpropionic acid, phenylacetic acid, benzoic acid and9-fluorenecarboxylic acid.

The term "carbocyclic group" includes monocyclic and polycyclic aromatichydrocarbon groups which preferably contain a maximum of 14 carbon atomin the cyclic structure and which can carry one or more substituentsselected from the group consisting of halogen, hydroxy, C₁₋₄ -alkyl,C₁₋₄ -alkoxy, trifluoro-methyl, phenyl, C₁₋₄ -alkylphenyl, halophenyl,nitro, amino, acylamino, benzyloxy and O-phosphate for example, phenyl,2-fluorophenyl, 2-bromophenyl, 2-chlorophenyl, 4-bromophenyl,2,6-dichlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 4-tolyl,2,3-dimethylphenyl, 2,6-dimethyl-phenyl, 2,3,5,6-tetramethylphenyl,2-methoxyphenyl, 3,5-dimethoxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-nitrophenyl,3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 2-acetamidophenyl,2-biphenylyl, 4-biphenylyl, 4-chloro-3-nitrophenyl,2-chloro-4-nitrophenyl, 4-hydroxy-2,6-dimethylphenyl,3-chloro-4-biphenylyl, 1-naphthyl and 2-naphthyl, and monocyclic andpolycyclic cycloalkyl groups which preferably contain a maximum of 13carbon atoms in the cyclic structure and which, when monocyclic, cancarry one or two fused benzene rings, for example, cyclopentyl,cyclohexyl, adamantyl, indanyl and fluorenyl.

The term "heterocyclic group" includes 5- and 6-membered saturated,partially unsaturated and aromatic heterocyclic groups which containoxygen, nitrogen or sulfur, which can carry a fused benzene ring andwhich can be substituted by one or more of the substituents mentionedearlier in connection with the carbocyclic group R⁴. Examples of suchheterocyclic groups are 2-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 2-benzofuranyl. 2,3-dihydro-2-benzofuranyl, 2-benzothienyl,2-quinolyl and 2-benzopyranyl.

Examples of "C₁₋₈ -alkylene" groups are --CH₂ --, --CH₂ CH₂ --,--CH(CH₃)--, --C(CH₃)₂ --, --CH(C₂ H₅)--, --CH₂ CH₂ CH₂ --, --CH₂--CH(CH₃)-- and --CH₂ CH₂ CH₂ CH₂ --.

It will be appreciated that, depending on the significance of A informula I, the compounds of this invention can be present asdiastereoisomers and that such diastereoisomers also form part of theinvention.

In formula I above R¹ preferably is C₁₋₄ -alkyl, especially ethyl orpropyl. R² preferably is hydroxy. R³ preferably is hydrogen. R⁴preferably is phenyl optionally substituted by one or more substituentsselected from halogen, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, trifluoromethyl,phenyl and nitro. Preferably, m stands for zero. X preferably is O. Ypreferably is a group of formula (a) above.

Particularly preferred compounds of formula I of the invention are thosein which R¹ is ethyl, R² is hydroxy, R³ is hydrogen, R⁴ is2-bromophenyl, 2,6-dichlorophenyl or 4-biphenylyl, m stands for zero, Xis O and Y is a group of formula (a) in which A is --CH₂ -- or--CH(CH₃)-- and n stands for zero. Further preferred compounds offormula I of the invention are those in which R¹ is ethyl or propyl, R²is hydroxy, R³ is hydrogen, R⁴ is 2-biphenylyl, 2,4-dichlorophenyl,2,4,5-trichlorophenyl, 4-chloro-2-nitrophenyl or2,4-dichloro-5-methoxyphenyl, m is zero, X is O and Y is a group offormula (a) in which A is --CH(CH₃)-- or --CH(phenyl)--, Z is O and n is1.

Particularly preferred compounds provided by the invention are:

5'-[2-(2-Bromophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine and

5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(4-biphenylyl)acetamido]-2',5'-dideoxy-5-ethyluridine.

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-phenylphenoxy)propionamido]uridine,

1-[5-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil,

5'-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(4-chloro-2-nitrophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,4-dichlorophenoxy)-2-phenylacetamido]-2',5'-deoxy-5-ethyluridine,

5'-[2-(RS)-(2,4-dichloro-5-methoxyphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridineand

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-propyluridine.

Examples of other interesting compounds provided by the invention are:

2',5'-Dideoxy-5-ethyl-5'-(2-phenylacetamido)uridine,

5'-(4-bromobenzamido)-5'-deoxythymidine,

5'-deoxy-5'-(4-nitrobenzamido)thymidine,

5'-benzamido-5'-deoxythymidine,

5'-deoxy-5'-(2-fluorobenzamido)thymidine,

5'-deoxy-5'-(2-nitrobenzamido)thymidine,

5'-[2-(2-bromophenyl)acetamido]-5'-deoxythymidine,

5'-deoxy-5'-[2-(4-nitrophenyl)acetamido]thymidine,

5'-deoxy-5'-(2-phenylacetamido)thymidine,

5'-deoxy-5'-[2-(4-trifluoromethylphenyl)acetamido]thymidine,

5'-benzamido-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-(2-fluorobenzamido)uridine,

5'-(2-bromobenzamido)-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-(4-nitrobenzamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(2-trifluoromethylbenzamido)uridine,

2',5'-dideoxy-5-ethyl-5'-[2-(2,6-dimethylphenyl)acetamido]uridine,

5'-[2(RS)-(2-bromophenyl)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2-chloro-3-nitrophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,6-dichlorophenyl)propionamido]-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-[2-(3,5-dimethylphenyl)acetamido]uridine,

2',5'-dideoxy-5'-[2-(3,5-dimethoxyphenyl)acetamido]-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-[2-(2,3,5,6-tetramethylphenyl)acetamido]uridine,

2',5'-dideoxy-5-ethyl-5'-[2-(2-methoxyphenyl)acetamido]uridine,

2',5'-dideoxy-5-ethyl-5'-[2-(2-nitrophenyl)]acetamidouridine,

5-bromo-5'-(2-(2-bromophenyl)acetamido]-2',5'-dideoxyuridine,

3'-O-butyryl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-3'-O-(3,3-dimethylbutyryl)-5-ethyluridine,

5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyl-3'-O-palmitoyluridine,

3'-O-acetyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

3'-O-benzyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine,

2',3',5'-trideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-5-ethyluridine,

5'-[2-(2-aminophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2-acetamidophenyl)acetamido]-3'-O-acetyl-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2-acetamidophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridine

5-(2-chloroethyl)-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine

5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2,6-dichlorophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2-bromophenyl)-N-methylpropionamido]-2',5'-dideoxy-5-ethyluridine,

3'-O-acetyl-5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-(2-naphthalamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(2-phenylbenzamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(3-phenylpropionamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(4-phenylbutyramido)uridine,

2',5'-dideoxy-5'-cinnamamido-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-(3-phenyl-2-propynamido)uridine,

2',5'-dideoxy-5-ethyl-5'-[3-(phenylsulfonyl)propionamido]uridine,

5'-(2-bromocinnamamido)-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-[2-(2-thienyl)acetamido]uridine,

2',5'-dideoxy-5-ethyl-5'-[2-(3-thienyl)acetamido]uridine,

5'-(1-adamantylcarboxamido)-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-(2-pyridylcarboxamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(3-pyridylcarboxamido)uridine,

2',5'-dideoxy-5-ethyl-5'-[2-(phenylsulphonyl)acetamido]uridine,

2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine,

3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine,

3'-O-butyryl-2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine,

2',5'-dideoxy-5-ethyl-3'-O-(3,3-dimethylbutyryl)-5'-(9-fluorenylcarboxamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)-3'-O-(hexadecanoyl)uridine,

2',5'-dideoxy-5-ethyl-3'-O-(9-fluorenylcarbonyl)-5'-(9-fluorenylcarboxamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(2-phenylbutyramido)uridine,

2',5'-dideoxy-5-ethyl-5'-(3-phenylbutyramido)uridine,

2',5'-dideoxy-5-ethyl-5'-(2,2-diphenylacetamido)uridine,

5'-(2-cyclohexyl-2-phenylacetamido)-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5'-ethyl-5'-(triphenylacetamido)uridine,

2',5'-dideoxy-5-ethyl-5'-(2-methyl-2-phenylpropionamido)uridine,

2',5'-dideoxy-5-ethyl-5'-[2(RS)-phenylpropionamido)]uridine,

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,6-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(3,5-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2-chlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2,6-dichlorophenoxy)acetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2,4-dichlorophenoxy)acetamido]-2',5'-dideoxy-5-ethyluridine,

5'-[4-(2,6-dichlorophenoxy)butyramido]-2',5'-dideoxy-5-ethyluridine,

5'-[6-(2,6-dichlorophenoxy)hexanamido]-2',5'-dideoxy-5-ethyluridine,

5'-[5-(2,6-dichlorophenoxy)valeramido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2-chloro-4-nitrophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2-chloro-4-phenylphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine

5-bromo-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxycytidine, and

5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethylcytidine.

Examples of additional, interesting compounds provided by the inventionare:

5'-[2-(2,6-dichlorophenyl)acetamido]-5'-deoxythymidine,

5-bromo-5'-[2(RS)-(2,,4-dichlorophenoxy)propionamido]-2',5'-dideoxyuridine,

5-bromo-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine,

5'-benzamido-5-bromo-2',5'-dideoxyuridine,

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-iodouridine,

5'-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxy-5-iodouridine

5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-iodouridine,

3'-O-benzyl-5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine,

5'-[2(RS)-(2,4-dichlorophenoxy)-N-methylpropionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(R)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(S)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,4-dichlorophenoxy)butyramido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(4-acetamido-2-chlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine.

5'-[2(RS)-(2-chloro-4-methoxyphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-methylbiphenylyloxy)propionamido]uridine

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-5'-deoxythymidine,

5'-[2-(2,4-dichlorophenoxy)-2-methylpropionamido]-2',5'-dideoxy-5-ethyluridine,

2',5'-dideoxy-5-ethyl-5'-[2(RS)-phenoxypropionamido]uridine,

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-fluorophenoxy)propionamido]uridine,

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-trifluoromethylphenoxy)propionamido]uridine,

1-[5-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]thymine,

5'-[2(RS)-(2,4-dichlorophenylsulphinyl)propionamido]2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,4-dichlorophenylsulphonyl)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2-(2,6-dichlorophenylacetamido)ethyl]-2',5'-dideoxy-5-ethyluridine,

5'-[2-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]-ethyl]-2',5'-dideoxy-5-ethyluridine,

5'-[2-[2(RS)-(2,4-dichlorophenoxy)propionamido]ethyl]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,6-dichlorobenzyl)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[2(RS)-(2,4-dichlorobenzyl)propionamido]-2',5'-dideoxy-5-ethyluridine,

5'-[5-chloro-2,3-dihydro-2-(RS)-benzofuranylcarboxamido]-2',5'-dideoxy-5-ethyluridine,

5-(6-chloro-2H-1-benzopyran-2-ylcarboxamido)-2',5'-dideoxy-5-ethyluridine,

5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

3'-O-acetyl-5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,

3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridine,

2',5'-dideoxy-5-ethyl-5'-[2-(2,6-dimethyl-4-phosphatophenyl)acetamido]uridine,

5-(2-chloroethyl)-2',5'-dideoxy-5'-[2-(2,4-dichlorophenyl)propionamido]uridine,

5'-benzamido-5-(2-chloroethyl)-2',5'-dideoxyuridine,

5-(2-chloroethyl)-5'-[2-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxyuridine,

5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-propyluridine,

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-propyluridineand

5-acetyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine.

According to the process provided by the present invention, thecompounds of formula I above and their tautomers can be prepared by

(a) reacting a compound of the formula ##STR4## wherein R¹, R², R³, R⁵,m and X have the significance given earlier, or a tautomer thereof inwhich any 4-amino group present is optionally protected, with a reactivederivative of an acid of the formula

    R.sup.4 --Y--COOH                                          III

wherein R⁴ and Y have the significance given earlier, and cleaving anyprotecting group present in the product, or

(b) for the preparation of a compound of formula I or a tautomer thereofin which X is O and R² is acyloxy, acylating a compound of formula I ora tautomer thereof in which X is O and R² is hydroxy, or

(c) for the preparation of a compound of formula I or a tautomer thereofin which X is O and R² is hydroxy, deacylating a compound of formula Ior a tautomer thereof in which X is O and R² is acyloxy, or

(d) for the preparation of a compound of formula I or a tautomer thereofin which Y is a group of formula (a) in which Z is SO or SO₂ and nstands for 1, oxidizing a compound of formula I or a tautomer thereof inwhich Y is a group of formula (a) in which Z is S and n stands for 1,and

(e) if desired, functionally modifying a reactive substituent present inR⁴.

A 4-amino group present in a starting material used in embodiment (a)the above process, that is, in a cytidine derivative, can be protectedby a readily cleavable protecting group, particularly an acyl group andespecially a benzoyl group.

The reactive derivative of an acid of formula III can be anyconventional reactive derivative, for example, an acid halide, an acidanhydride or a reactive derivative formed by activating the acid withdicyclohexylcarbodiimide or a similar activating reagent. In a preferredembodiment, an acid halide, particularly an acid chloride, is used asthe reactive derivative.

The reaction in accordance with embodiment (a) of the process can becarried out in a known manner. The reaction can be carried out in thepresence or absence of an inert organic solvent. When such a solvent isused, this can suitably be an ether such as diethyl ether, an aromatichydrocarbon such as benzene, or the like. The reaction is expedientlycarried out in the presence of an inorganic base such as an alkali metalhydroxide, for example, sodium hydroxide or potassium hydroxide, or atertiary organic base, for example, pyridine. Conveniently, the reactionis carried out at a temperature in the range of from about 0° C. to roomtemperature.

When a starting material containing a protected 4-amino group is used,the protecting group is cleaved from the reaction product in aconventional manner. For example, an acyl group such as the benzoylgroup can be cleaved by treatment with alcoholic ammonia solution,particularly methanolic ammonia solution, at about room temperature.

The acylation in accordance with embodiment (b) of the process can alsobe carried out in a known manner, for example, using an appropriatereactive derivative of an acid such as an acid halide, for example, anacid chloride, an acid anhydride or the like. Suitably, the acylation iscarried out in the presence of a base, which is suitably a tertiaryorganic base such as pyridine, 4-dimethylaminopyridine or the like andat a temperature in the range of from about 0° C. to room temperature.

The deacylation in accordance with embodiment (c) of the process canlikewise be carried out in a known manner, for example, using analcoholic ammonia solution, for example, a methanolic ammonia solution,at about room temperature.

The oxidation in accordance with embodiment (d) of the process can alsobe carried out in a known manner. For example, the oxidation can becarried out using an organic peracid such as peracetic acid, perbenzoicacid, m-chloroperbenzoic acid, perphthalic acid or the like, expedientlyin a suitable solvent such as a halogenated hydrocarbon, for example,chloroform, or an alkanoic acid, for example, acetic acid, and at atemperature in the range of from about 0° C. to room temperature. Whenperacetic acid is used for the oxidation, this can conveniently beprepared in situ from glacial acetic acid and hydrogen peroxide. When 1equivalent of an organic peracid is used there is obtained a compound offormula I or a tautomer thereof in which Z represents --SO--, whereasthe use of 2 equivalents of organic peracid leads to a compound offormula I or a tautomer thereof in which Z represents --SO₂ --.

In accordance with embodiment (e) of the process a reactive substituentpresent in R⁴ can be functionally modified. Such modifications can becarried out according to known procedures. For example, when R⁴ containsa nitro group, this can be reduced by catalytic hydrogenation to anamino group. Again, when R⁴ contains an amino group, this can beacylated to an acylamino group. Further, when R⁴ contains a benzyloxygroup, this can be converted into a hydroxy group by debenzylation usinghydrogen in the presence of a catalyst. Yet again, when R⁴ contains ahydroxy group, this can be converted into an O-phosphate group bytreatment with dibenzylphosphoryl chloride followed by debenzylationusing hydrogen in the presence of a catalyst.

The starting materials used in the process provided by the invention areknown compounds or analogs of known compounds which can be prepared in asimilar manner to the known compounds. Further, certain of the Exampleshereinafter contain detailed information concerning the preparation ofthe respective starting materials.

The compounds of formula I and their tautomers possess antiviralactivity and can be used in the control or prevention of viralinfections, for example, herpes simplex viral infections.

The in vitro activity of the compounds of formula I and their tautomersin inhibiting herpes simplex virus type 2 (HSV-2) thymidine kinase canbe demonstrated by means of the following test procedure:

In this test, the assay mixture contains 50 nM Tris-HCl, pH 8, 5 mMmagnesium chloride, 5 mM ATP, 0.3 μM ³ H-thymidine (50 Ci/mmol),suitably diluted thymidine kinase extract and various concentrations ofa compound of formula I or a tautomer thereof in a total volume of 100μl. Assays are incubated at 37° C. for 30 minutes and the reaction isterminated by immersion in a boiling water bath for 2 minutes. 85 μlaliquots from each assay are then dried on to DEAE-cellulose paper discsand the unphosphorylated ³ H-thymidine is removed by washing in 4 mMammonium formate. The radioactivity remaining bound to the discs is thenmeasured by scintillation spectrophotometry. The degree of inhibition ateach concentration of compound of formula I or tautomer thereof isexpressed as a percentage of the control reaction (100%) aftersubstracting a measured blank value which represents the amount ofradioactivity bound to the disc from a reaction containing heatinactivated enzymes. the IC₅₀ value, namely, the concentration ofcompound of formula I or tautomer thereof which inhibits enzyme activityby 50%, is then calculated. The results obtained with representativecompounds of formula I are complied in the following Table:

                  Table                                                           ______________________________________                                        Compound of formula I                                                                           IC.sub.50 (μM)                                           ______________________________________                                        A                 0.02                                                        B                 0.003                                                       C                 0.0037                                                      D                 0.07                                                        E                 0.005                                                       F                 0.004                                                       G                 0.0013                                                      H                 0.0027                                                      I                 0.0047                                                      J                 0.0012                                                      K                 0.0035                                                      ______________________________________                                         Compound A: 5[2(2-Bromophenyl)acetamido2',5dideoxy-5-ethyluridine.            Compound B: 5[2(2,6-Dichlorophenyl)acetamido2',5dideoxy-5-ethyluridine.       Compound C:                                                                   5[2(RS)(2,4-Dichlorophenoxy)propionamido2',5dideoxy-5-ethyluridine.           Compound D: 5[2(4-Biphenylyl)acetamido2',5dideoxy-5-ethyluridine.             Compound E:                                                                   2',5Dideoxy-5-ethyl-5[2(RS)(2-phenylphenoxy)propionamido]uridine.             Compound F:                                                                   1[5[2(RS)(2,4-Dichlorophenoxy)propionamido2,5-dideoxy-2-fluoro-D-arabinof    ranosyl5-ethyluracil.                                                          Compound G:                                                                   5[2(RS)(2,4,5-Trichlorophenoxy)propionamido2',5dideoxy-5-ethyluridine.        Compound H:                                                                   5[2(RS)(4-Chloro-2-nitrophenoxy)propionamido2',5dideoxy-5-ethyluridine.       Compound I:                                                                   5[2(RS)(2,4-Dichlorophenoxy)-2-phenylacetamido2',5deoxy-5-ethyluridine.       Compound J:                                                                   5[2(RS)(2,4-Dichloro-5-methoxyphenoxy)propionamido2',5dideoxy-5-ethylurid    ne.                                                                            Compound K:                                                                   5[2(RS)(2,4-Dichlorophenoxy)propionamido2',5dideoxy-5-propyluridine.     

The compounds of formula I and their tautomers can be used asmedicaments in the form of pharmaceutical preparations which containthem in association with a compatible pharmaceutical carrier material.This can be an organic or inorganic carrier suitable for enteral, forexample, oral or parenteral administration. Examples of such carriersare water, gelatin, gum arabic, lactose, starch, magnesium stearate,talc, vegetable oils, polyalkylene glycols and petroleum jelly. Thepharmaceutical preparations can be made up in a solid form, for example,as tablets, dragees, suppositories or capsules, or in a liquid form, forexample, as solutions, suspensions or emulsions, they may be subjectedto standard pharmaceutical operations, for example, sterilization and/ormay contain adjuvants, for example, preserving, stabilizing, wetting oremulsifying agents, salts for varying the osmotic pressure or buffers.They may also contain other therapeutically valuable substances.

The compounds of formula I and their tautomers can be administered to anadult warm-blooded animal in a daily dosage of from about 1 mg to 1000mg, preferably about 5 mg to 500 mg. The daily dosage may beadministered as a single dose or in divided doses. The above dosagerange is given by way of example only and can be varied upwards ordownwards depending on factors such as the particular compound beingadministered, the route of administration, the severity of theindication being treated and the condition of the patient.

The examples which follow further illustrate the invention. Alltemperatures are in degrees centigrade, unless otherwise stated.

EXAMPLE 1

(A) A solution of 219 mg of 4-bromobenzoyl chloride in 5 ml of diethylether was added to a solution of 241 mg of 5'-amino-5'-deoxythymidine in4 ml of 0.25M sodium hydroxide solution and the mixture was shakenvigorously for 10 minutes. The mixture was filtered and the solid waswashed with 10 ml of water and 4 ml of diethyl ether, and recrystallizedfrom ethanol to give 195 mg of 5'-(4-bromobenzamido)-5'-deoxythymidineof melting point 250.5°-252° C.

(B) In an analogous manner, there were obtained:

(a) from 4-nitrobenzoyl chloride and 5'-amino-5'-deoxythymidine:5'-deoxy-5'-(4-nitrobenzamido)thymidine, mp 230° C.;

(b) from benzoyl chloride and 5'-amino-5'-deoxythymidine:5'-benzamido-5'-deoxythymidine, mp 234°-235° C.;

(c) from 2-fluorobenzoyl chloride and 5'-amino-5'-deoxythymidine:5'-deoxy-5'-(2-fluorobenzamido)thymidine, mp 228°-228.5° C.; and

(d) from 2-nitrobenzoyl chloride and 5'-amino-5'-deoxythymidine:5'-deoxy-5'-(2-nitrobenzamido)thymidine, mp 190°-191° C.

EXAMPLE 2

(A) 140 mg of benzoyl chloride were added to a solution of 255 mg of5'-amino-2',5'-dideoxy-5-ethyluridine in 3 ml of 0.33M sodium hydroxidesolution and the mixture was shaken vigorously for 5 minutes. Themixture was filtered and the solid was washed with 5 ml of water and 5ml of diethyl ether, and recrystallized from ethanol to give 140 mg of5'-benzamido-2',5'-dideoxy-5-ethyluridine of melting point 246°-247° C.

(B) In an analogous manner, there were obtained:

(a) from 2-fluorobenzoyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-(2-fluorobenzamido)uridine, mp 216°-216.5° C.;

(b) from 2-bromobenzoyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:5'-(2-bromobenzamido)-2',5'-dideoxy-5-ethyluridine, mp 237°-238° C.;

(c) from 4-nitrobenzoyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-(4-nitrobenzamido)uridine, mp 250°-250.5° C.;and

(d) from 2-trifluoromethylbenzoyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-(2-trifluoromethylbenzamido)uridine, mp263°-264° C.

EXAMPLE 3

(A) A solution of 1.12 g of (2,6-dichlorophenyl)acetyl chloride in 15 mlof diethyl ether was added to a solution of 1.275 g of5'-amino-2',5'dideoxy-5-ethyluridine in 15 ml of 0.33M sodium hydroxidesolution. The mixture was shaken vigorously for 10 minutes and thenfiltered. The solid was washed with 150 ml of water, 20 ml of ethanoland 40 ml of diethyl ether, and then recrystallized from 2.5 l ofethanol to give 1.53 g of5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in theform of a white solid of melting point 296°-297° C.

(B) In an analogous manner, there were obtained:

(a) from (2,6-dimethylphenyl)acetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-[2-(2,6-dimethylphenyl)acetamido]uridine, mp282° C.;

(b) from 2(RS)-(2-bromophenyl)propionyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:5'-[2(RS)-(2-bromophenyl)propionamido]-2',5'-dideoxy-5-ethyluridine, mp236°-236.5° C.;

(c) from 4-biphenylylacetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:5'-[2-(4-biphenylyl)acetamido]-2',5'-dideoxy-5-ethyluridine, mp 244° C.;

(d) from (2-chloro-3-nitrophenyl)acetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:5'-[2-(2-chloro-3-nitrophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,mp 240°-241.5° C.;

(e) from 2(RS)-(2,6-dichlorophenyl)propionyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:5'-[2(RS)-(2,6-dichlorophenyl)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 193°-194° C.;

(f) from (3,5-dimethylphenyl)acetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-[2-(3,5-dimethylphenyl)acetamido]uridine, mp234°-236° C.;

(g) from (3,5-dimethoxyphenyl)acetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5'-[2-(3,5-dimethoxyphenyl)acetamido]-5-ethyluridine, mp219°-220.5° C.;

(h) from (2,3,5,6-tetramethylphenyl)acetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-[2-(2,3,5,6-tetramethylphenyl)acetamido]uridine,mp 288° C.;

(i) from (2-bromophenyl)acetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine, mp247°-248° C.;

(j) from (2-methoxyphenyl)acetyl chloride and540-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-[2-(2-methoxyphenyl)acetamido]uridine, mp222°-224° C.;

(k) from (2-nitrophenyl)acetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-[2-(2-nitrophenyl)acetamido]uridine, mp240°-241° C.;

(l) from phenylacetyl chloride and5'-amino-2',5'-dideoxy-5-ethyluridine:2',5'-dideoxy-5-ethyl-5'-(2-phenylacetamido)uridine, mp 218°-219° C.;and

(m) from 2,6-dichlorophenylacetyl chloride and5'-amino-5'-deoxythymidine:5'-[2-(2,6-dichlorophenyl)acetamido]-5'-deoxythymidine, mp 276° C.

EXAMPLE 4

(A) A suspension of 108 mg of (2-bromophenyl)acetic acid and 1 ml ofoxalyl chloride in 2.5 ml of benzene was stirred and 1 drop ofdimethylformamide was added. The mixture was stirred at room temperaturefor 1.5 hours and then evaporated. The residue was taken up in 3 ml ofdiethyl ether and a solution of 153 mg of5'-amino-5-bromo-2',5'-dideoxyuridine in 4.5 ml of 0.11M sodiumhydroxide solution was added thereto. The mixture was shaken vigorouslyfor 10 minutes and then filtered. The solid was recrystallized fromethanol to give 75 mg of5-bromo-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxyuridine in the formof a white solid of melting point 222°-223° C.

(B) In an analogous manner, there were obtained:

(a) from 2(RS)-(2,4-dichlorophenoxy)propionic acid and5'-amino-5-bromo-2',5'-dideoxyuridine:5-bromo-5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxyuridine,mp 171°-172° C.;

(b) from 2,6-dichlorophenylacetic acid and5'-amino-5-bromo-2',5'-dideoxyuridine:5-bromo-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine, mp232°-233° C.;

(c) from benzoic acid and 5'-amino-5-bromo-2',5'-dideoxyuridine:5'-benzamido-5-bromo-2',5'-dideoxyuridine, mp 221°-222° C.;

(d) from 2(RS)-(2,4-dichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-iodouridine:5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-iodouridine,mp 205°-207° C.;

(e) from 2(RS)-(2,4,5-trichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-iodouridine:5'-[2(RS)-2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxy-5-iodouridine,mp 214°-215° C.; and

(f) from 2,6-dichlorophenylacetic acid and5'-amino-2',5'-dideoxy-5-iodouridine:5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-iodouridine, mp225° C.

EXAMPLE 5

0.84 ml of a 1M sodium hydroxide solution was added to a solution of 256mg of 5'-amino-5-bromo-2',5'-dideoxycytidine in 3.3 ml of water. Asolution of (2-bromophenyl)acetyl chloride (prepared from 185 mg of theacid) in 5 ml of dichloromethane was added, the mixture was shakenvigorously for 10 minutes and then filtered. The solid wasrecrystallized from 30 ml of ethanol to give 44 mg of5-bromo-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxycytidine in theform of a white solid of melting point 164°-167° C.

The 5'-amino-5-bromo-2',5'-dideoxycytidine used as the starting materialwas prepared as follows:

A solution of 3.06 g of 5-bromo-2'-deoxycytidine and 2.3 g ofp-toluenesulfonyl chloride in 50 ml of pyridine was stirred at 4° C. for24 hours. An additional 1.91 g of p-toluenesulfonyl chloride were addedand stirring was continued at 4° C. for an additional 22 hours. 20 ml ofmethanol were added, the mixture was stirred at room temperature for 30minutes and then evaporated. The crude product was subjected to flashchromatography on a column of silica gel using ethyl acetate/methanol(9:1) for the elution, there being obtained 2.26 g of5-bromo-2'-deoxy-5'-O-p-toluenesulfonylcytidine in the form of a whitesolid of melting point 168° C. (decomposition).

A solution of 2.19 g of the above solid and 354 mg of lithium azide in26 ml of dimethylformamide was stirred at 75° C. for 2 hours. Thesolvent was removed by evaporation and the residue was triturated withdiethyl ether to give 1.351 g of 5'-azido-5-bromo-2',5'-dideoxycytidinein the form of a white solid of melting point 192°-193° C.(decomposition).

A solution of 1.30 g of the above solid and 1.648 g oftriphenylphosphine in 50 ml of pyridine was stirred at room temperaturefor 100 minutes. 5 ml of ammonium hydroxide solution were added, themixture was stirred for an additional 3 hours and then evaporated. Theresidue was washed four times with 40 ml of toluene each time and fourtimes with 40 ml of diethyl ether each time, and then extracted twicewith 125 ml of water each time. The combined aqueous extracts wereevaporated, the residue was dissolved in 25 ml of ethanol and thesolution was diluted with 300 ml of diethyl ether, whereby a white solidprecipitated. After standing at 0° C. overnight, the solid was collectedby filtration to give 0.53 g of 5'-amino-5-bromo-2',5'-dideoxycytidinein the form of a white powder which decomposed above 115° C.

EXAMPLE 6

(A) A mixture of 400 mg of5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine, 0.15ml of butyryl chloride and 1 mg of 4-dimethylaminopyridine in 50 ml ofpyridine was stored at room temperature overnight and then evaporated.The residue was subjected to flash chromatography on a column of silicagel using dichloromethane/methanol (24:1) for the elution, there beingobtained 175 mg of3'-O-butyryl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridinein the form of a white solid of melting point 130°-132° C.

(B) In an analogous manner, there were obtained:

(a) from5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine and3,3-dimethylbutyryl chloride:

2',5'-dideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-3'-O-(3,3-dimethylbutyryl)-5-ethyluridine,mp 77°-79° C.;

(b) from5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine andpalmitoyl chloride:

5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyl-3'-O-palmitoyluridine,mp 150° C.; and

(c) from5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine andacetyl chloride:

3'-O-acetyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,mp 193°-194° C.

EXAMPLE 7

(A) A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103mg of the acid) in 2 ml of diethyl ether was added to a solution of 173mg of 5'-amino-3'-O-benzyl-2',5'-dideoxy-5-ethyluridine in 4.5 ml of0.11M sodium hydroxide solution. The mixture was shaken vigorously for10 minutes and then filtered. The solid was recrystallized from ethanolto give 120 mg of3'-O-benzyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridinein the form of a white solid of melting point 174°-177° C.

(B) In an analogous manner, from 2(RS)-(2,4-dichlorophenoxy)propionicacid and 5'-amino-3'-O-benzyl-2',5'-dideoxy-5-ethyluridine there wasobtained3'-O-benzyl-5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridineof melting point 195°-200° C.

The 5'-amino-3'-O-benzyl-2',5'-dideoxy-5-ethyluridine used above as thestarting material was prepared as follows:

A mixture of 6.5 g of 2'-deoxy-5-ethyl-5'-O-trityluridine, 19 g ofpowdered potassium hydroxide and 9.5 ml of benzyl chloride in a mixtureof 60 ml of benzene and 21 ml of dioxane was stirred and heated underreflux for 4 hours. After cooling 65 ml of water and 20 ml of aceticacid were added and the phases were separated. The organic phase waswashed twice with 90 ml of water each time, dried over anhydrous sodiumsulfate and evaporated to give 4.5 g of3'-O-benzyl-2'-deoxy-5-ethyl-5'-O-trityluridine in the form of a stickysolid.

A solution of the above product in a mixture of 32 ml of acetic acid and8 ml of water was stirred and heated under reflux for 10 minutes. Themixture was cooled to 0° C. and filtered. The filtrate was trituratedwith 100 ml of water to give a sticky solid. This was subjected to flashchromatography on a column of silica gel using ethyl acetate for theelution. The product was crystallized from a mixture of acetone andpetroleum ether (boiling point 60°-80° C.) to give 1.25 g of3'-O-benzyl-2'-deoxy-5-ethyluridine in the form of a colorlessglass-like solid.

A mixture of 1.2 g of the above product, 929 mg of triphenylphosphine,1.131 g of sodium azide and 1.179 g of carbon tetrabromide in 14 ml ofdimethylformamide was stirred at room temperature for 20 hours. 8 ml ofmethanol were added, the mixture was stirred for 30 minutes and thenevaporated. The residue was suspended in 80 ml of water and extractedthree times with 60 ml of ethyl acetate each time. The combined ethylacetate extracts were washed with water, dried over anhydrous sodiumsulfate and evaporated. The residue was subjected to flashchromatography on a column of silica gel using ethyl acetateacetate/hexane (2:1) for the elution, there being obtained 1.20 g of5'-azido-3'-O-benzyl-2',5'-dideoxy-5-ethyluridine in the form of acolorless gum.

A solution of 1.40 g of the above product and 1.582 g oftriphenylphosphine in 48 ml of pyridine was stirred at room temperaturefor 100 minutes. 5 ml of ammonium hydroxide solution were added, themixture was stirred at room temperature for an additional 3 hours andthen evaporated to dryness. The residue was crystallized from a mixtureof ethyl acetate and hexane to give a pale grey solid. This solid wassuspended in 30 ml of diethyl ether, the suspension was stirred for 1.5hours and then filtered to give 0.45 g of5'-amino-3'-O-benzyl-2',5'-dideoxy-5-ethyluridine in the form of a whitesolid of melting point 95° C. (decomposition).

EXAMPLE 8

(A) A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103mg of the acid) in 2 ml of diethyl ether was added to a solution of 140mg of 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in 2.5 ml of 0.2Msodium hydroxide solution, the mixture was shaken vigorously for 10minutes and then filtered. The solid was washed with 5 ml of water and50 ml of diethyl ether, and then recrystallized from acetone to give 60mg of5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridinein the form of a white solid of melting point 249°-250° C.

(B) In an analogous manner, from 2(RS)-(2,4-dichlorophenoxy)propionylchloride (prepared from the acid) and5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine, there was obtained5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridineof melting point 121°-124° C.

The 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine used above as thestarting material was prepared as follows:

A mixture of 6 g of 2'-deoxy-5-ethyl-5'-O-trityluridine, 1.347 g ofpowdered potassium hydroxide and 1.95 ml of ethyl iodide in a mixture of60 ml of benzene and 20 ml of dioxane was stirred and heated underreflux for 14 hours. The solvents were removed by evaporation, theresidue was taken up in 6 ml of methanol and the solution was pouredinto 250 ml of water. The resulting mixture was extracted four timeswith 150 ml of chloroform each time and the combined chloroform extractswere evaporated to give 2'-deoxy-3'-O-ethyl-5-ethyl-5'-O-trityluridinewhich was used directly in the next step.

A solution of the above product in a mixture of 52 ml of acetic acid and13 ml of water was stirred and heated under reflux for 1 hour and thenevaporated to dryness. The residue was subjected to flash chromatographyon a column of silica gel using ethyl acetate for the elution, therebeing obtained 1.57 g of 2'-deoxy-3'-O-ethyl-5-ethyluridine in the formof a white solid of melting point 157° C.

A mixture of 1.40 g of 2'-deoxy-3'-O-ethyl-5-ethyluridine, 1.3 g oftriphenylphosphine, 1.59 g of sodium azide and 1.66 g of carbontetrabromide in 19 ml of dimethylformamide was stirred at roomtemperature for 20 hours. 11 ml of methanol were added, the mixture wasstirred for 30 minutes and then evaporated. The residue was suspended in110 ml of water and extracted three times with 70 ml of ethyl acetateeach time. The combined ethyl acetate extracts were evaporated and theresidue was subject to flash chromatography on a column of silica gelusing ethyl acetate/hexane (2:1) for the elution, there being obtained1.26 g of 5'-azido-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in the formof a colorless oil.

A solution of 1.26 g of the above oil in 100 ml of methanol washydrogenated over 10% palladium-on-carbon catalyst at room temperatureand under atmospheric pressure for 4.5 hours. The catalyst was removedby filtration and the filtrate was evaporated. The residue wasrecrystallized from a mixture of ethyl acetate and hexane to yield 780mg of 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in the form of awhite solid of melting point 122°-123° C.

EXAMPLE 9

A solution of 210 mg of (2-bromophenyl)acetyl chloride in 3 ml ofdiethyl ether was added to a solution of 324 mg of5'-amino-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine in 4.9 ml of 0.18Msodium hydroxide solution and the mixture was shaken vigorously for 10minutes. The solid was collected by filtration, washed with 2 ml ofwater and 1 ml of diethyl ether and recrystallized from 15 ml of ethanolto give 100 mg of4-N-benzoyl-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethylcytidinein the form of a white solid which was processed further withoutpurification.

A solution of 100 mg of the above solid in 20 ml of methanolic ammoniasolution was stored at room temperature overnight. It was thenevaporated to dryness and the residue was triturated with 20 ml ofdiethyl ether to give 52 mg of5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethylcytidine in form ofa white solid of melting point 236°-237° C.

The 5'-amino-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine used as thestarting material was prepared as follows:

A solution of 4.08 g of 2'-deoxy-5-ethylcytidine in 200 ml of ethanolwas stirred and heated under reflux. 3.94 g of benzoic anhydride wereadded and additional portions, each of 3.94 g, of benzoic anhydride wereadded after 1, 2 and 4 hours. The mixture was heated under reflux for anadditional 1 hour after the final addition and was then evaporated todryness. The residue was suspended in 250 ml of diethyl ether and storedat room temperature overnight. The solid was collected by filtration andwashed with 75 ml of diethyl ether to give 4.5 g of4-N-benzoyl-2'-deoxy-5-ethylcytidine in the form of a white solid ofmelting point 172°-174° C.

A mixture of 1.436 g of N-benzoyl-2'-deoxy-5-ethylcytidine, 1.072 g oftriphenylphosphine, 1.304 g of sodium azide and 1.360 g of carbontetrabromide in 16 ml of dimethylformamide was stirred at roomtemperature for 20 hours. 8 ml of methanol were added, the mixture wasstirred for 30 minutes and then evaporated. The residue was suspended in80 ml of water and extracted three times with 100 ml of ethyl acetateeach time. The combined ethyl acetate extracts were washed with waterand evaporated. The residue was subjected to flash chromatography on acolumn of silica gel using ethyl acetate for the elution, there beingobtained 1 g of 5'-azido-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine inthe form of a white crystalline solid of melting point 125°-126° C.

A solution of 500 mg of the above product in 30 ml of methanol washydrogenated over 10% palladium-on-carbon catalyst at room temperatureand under atmospheric pressure for 4 hours. The catalyst was removed byfiltration and the filtrate was evaporated to yield5'-amino-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine in the form of acolorless gum.

EXAMPLE 10

A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 146 mgof the acid) in 1 ml of diethyl ether was added to a solution of 170 mgof 5'-amino-2',3',5'-trideoxy-5-ethyluridine in 2.72 ml of 0.26M sodiumhydroxide solution and the mixture was shaken for 10 minutes. Themixture was filtered and the solid was recrystallized from 20 ml ofethanol to give 150 mg of2',3',5'-trideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-5-ethyluridine inthe form of a white solid of melting point 237°-238° C.

The 5'-amino-2',3',5'-trideoxy-5-ethyluridine used as the startingmaterial was prepared as follows:

A solution of 16.0 g of 2'-deoxy-5-ethyl-5'-O-trityluridine and 6.8 mlof methanesulfonyl chloride in 140 ml of pyridine was stored at 0° C.overnight. 3 g of ice were added, the mixture was stored at 0° C. for 1hour and then poured into 1500 ml ice/water. The resulting solid wascollected by filtration, washed with 500 ml of water and dried to yield17.35 g of 2'-deoxy-5-ethyl-3'-O-methanesulfonyl-5'-O-trityluridine inthe form of a white solid which was used in the next step withoutfurther purification.

A mixture of 1.2 g of the above product and 681 mg of sodium iodide in10 ml of ethyl methyl ketone was stirred and heated under reflux for 7hours. The mixture was allowed to cool and was then filtered. Thefiltrate was evaporated to give a colorless gum which was subjected toflash chromatography on a column of silica gel using ethylacetate/hexane (2:1) for the elution. The product was crystallized froma mixture of ethyl acetate and hexane to give 360 mg of2',3'-dideoxy-5-ethyl-3'-iodo-5'-O-trityluridine in the form of whitecrystals of melting point 93°-98° C.

A solution of 720 mg of 2',3'-dideoxy-5-ethyl-3'-iodo-5'-O-trityluridinein a mixture of 16 ml of acetic acid and 4 ml of water was stirred andheated under reflux for 1 hour. The solvent was removed by evaporationand the residue was crystallized from a mixture of ethyl acetate andhexane to give 180 mg of 2',3'-dideoxy-5-ethyl-3'-iodouridine in theform of a white solid of melting point 161.5°-163° C.

A solution of 2.50 g of 2',3'-dideoxy-5-ethyl-3'-iodouridine in amixture of 90 ml of ethanolic ammonia and 17 ml of water washydrogenated over 5% palladium on barium sulfate catalyst at roomtemperature and under atmospheric pressure for 3 hours. The mixture wasfiltered and the filtrate was evaporated. The residue was extractedtwice with 250 ml of hot ethyl acetate each time and the combined ethylacetate extracts were evaporated. The residue was chromatographed on ashort column of silica gel using ethyl acetate for the elution and theproduct was crystallized from a mixture of ethyl acetate and hexane togive 1.17 g of 2',3'-dideoxy-5-ethyluridine in the form of a white solidof melting point 109°-113° C.

A mixture of 350 mg of 2',3'-dideoxy-5-ethyluridine, 391 mg oftriphenylphosphine, 475 mg of sodium azide and 496 mg of carbontetrabromide was stirred at room temperature for 20 hours. 3 ml ofmethanol were added, the mixture was stirred for 1 hour and thenevaporated. The residue was suspended in 30 ml of water and extractedtwice with 50 ml of ethyl acetate each time. The combined ethyl acetateextracts were washed with 20 ml of water and then evaporated. Theresidue was subjected to flash chromatography on a column of silica gelusing ethyl acetate for the elution. The product was crystallized from amixture of ethyl acetate and hexane to give 200 mg of5'-azido-2',3',5'-trideoxy-5-ethyluridine in the form of a white solidwhich was processed directly without further purification.

A solution of 190 mg of the above product in 25 ml of methanol washydrogenated over 100 mg of 10% palladium-on-carbon catalyst at roomtemperature and under atmospheric pressure for 4 hours. The catalyst wasremoved by filtration and the filtrate was evaporated to give 180 mg of5'-amino-2',3',5'-trideoxy-5-ethyluridine in the form of a colorlessgum.

EXAMPLE 11

A solution of 0.2 g of2',5'-dideoxy-5-ethyl-5'-[2-(2-nitrophenyl)acetamido]uridine in 100 mlof ethanol was hydrogenated over 0.1 g of 10% palladium-on-carboncatalyst at room temperature and under atmospheric pressure until theuptake of hydrogen was complete. The mixture was filtered and thefiltrate was evaporated to yield an oil which crystallized from ethanolto give 0.1 g of5'-[2-(2-aminophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the formof a white solid of melting point 195°-196° C.

EXAMPLE 12

A solution of 0.2 g of5'-[2-(2-aminophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in 5 ml ofdry pyridine was treated with 0.5 g of acetic anhydride and the mixturewas stored at room temperature for 17 hours. The mixture was thenevaporated to give an oil which crystallized from ethanol to yield 0.13g of5'-[2-(2-acetamidophenyl)acetamido]-3'-O-acetyl-2',5'-dideoxy-5-ethyluridinein the form of a buff colored solid of melting point 143°-145° C.

EXAMPLE 13

A solution of 0.2 g of5'-[2-(2-acetamidophenyl)acetamido]-3'-O-acetyl-2',5'-dideoxy-5-ethyluridinein 20 ml of methanol was treated with 20 ml of methanol saturated withammonia. The mixture was left to stand at room temperature for 17 hours.A white solid separated and was collected by filtration, washed twicewith 5 ml of ethanol each time and twice with 5 ml of diethyl ether eachtime and subsequently dried to give5'-[2-(2-acetamidophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine ofmelting point 266°-267° C.

EXAMPLE 14

In a manner analogous to that described in Example 1, there wereobtained:

(a) from 5'-amino-5'-deoxythymidine and (2-bromophenyl)acetyl chloride:

5'-[2-(2-bromophenyl)acetamido]-5'-deoxythymidine, mp 232°-233° C.;

(b) from 5'-amino-5'-deoxythymidine and (4-nitrophenyl)acetyl chloride:

5'-deoxy-5'-[2-(4-nitrophenyl)acetamido]thymidine, mp 240°-241° C.;

(c) from 5'-amino-5'-deoxythymidine and phenylacetyl chloride:

5'-deoxy-5'-(2-phenylacetamido)thymidine, mp 221°-222° C.; and

(d) from 5'-amino-5'-deoxythymidine and (4-trifluoromethylphenyl)acetylchloride:

5'-deoxy-5'-[2-(4-trifluoromethylphenyl)acetamido]thymidine, mp252°-253° C.

EXAMPLE 15

0.2 g of (4-hydroxy-2,6-dimethylphenyl)acetic acid in 10 ml of benzenewas treated with 0.15 g of oxalyl chloride and 1 drop ofdimethylformamide and the mixture was stirred for 2 hours. The solventwas removed by evaporation, the residue was cooled -20° C. and thendissolved in 6 ml of dry pyridine. 0.26 g of5'-amino-2',5'-dideoxy-5-ethyluridine was added and the mixture wasstirred at 0° C. for 4 hours and then left to stand at 4° C. overnight.The solvent was removed by evaporation and the residue was re-evaporatedwith toluene and water. The residue was triturated with water at 0° C.and the resulting solid was removed by filtration and dried in vacuo togive 0.175 g of crude product of melting point 232°-238° C.(decomposition). Recrystallization from 6 ml of methanol gave 0.06 g ofpure 2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridine of melting point240°-243° C. (decomposition).

EXAMPLE 16

0.32 g of 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloridewere dissolved in a mixture of 5 ml of water and 2.5 ml of 1M sodiumhydroxide solution. The mixture was shaken vigorously for 25 minuteswith a benzene solution of (2,6-dichlorophenyl)acetyl chloride (preparedfrom 0.22 g of the acid by treatment with oxalyl chloride). Theresulting solid was removed by filtration and washed with water and thenwith diethyl ether to give 0.29 g of crude product of melting point248°-249° C. (decomposition). 0.1 g of this solid was stirredsuccessively for 1 hour each time with 1 ml of water, 2 ml of ethanoland 2 ml of methanol to give 0.03 g of5-(2-chloroethyl)-5'-[2-(2,6-dichlorophenyl)-acetamido]-2',5'-dideoxyuridineof melting point 253°-254° C. (decomposition).

The 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride usedas the starting material was prepared as follows:

1.4 g of 5-(2-chloroethyl)-2'-deoxyuridine and 1.3 g oftriphenylphosphine were dissolved in 20 ml of dimethylformamide andstirred while 1.2 g of lithium azide were added to give a solutionwithin 5 minutes at room temperature. 1.7 g of carbon tetrabromide wereadded portionwise during 5 minutes to give a hazy orange coloredsolution which was stirred at room temperature for 17 hours. 5 ml ofmethanol were added to give a clear solution. After 0.5 hour, thesolvents were removed by evaporation under an oil pump vacuum to give agum which was partitioned between 30 ml of ethyl acetate and 20 ml ofwater. The white solid which formed was removed by filtration to give0.64 g of crude product of melting point 179°-182° C. (decomposition).This crude product was stirred with methanol and then removed byfiltration to give 0.48 g of pure5'-azido-2',5'-dideoxy-5-(2-chloroethyl)-uridine of melting point197°-199° C. (decomposition).

0.16 g of 5'-azido-2',5'-dideoxy-5-(2-chloroethyl)uridine was dissolvedin 100 ml of methanol and 1.9 ml of a 0.27M solution of hydrogenchloride in methanol was added. A slurry of 25 mg of 5%palladium-on-charcoal catalyst in 10 ml of ethanol was added under anitrogen atmosphere and the mixture was hydrogenated at room temperatureand under atmospheric pressure for 2 hours. The catalyst was removed byfiltration and the filtrate was evaporated to give a solid which, aftercrystallization from a mixture of 15 ml of methanol and 30 ml of diethylether, gave 0.13 g of 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridinehydrochloride melting point 229°-230° C. (decomposition).

EXAMPLE 17

0.72 g of 2',5'-dideoxy-5-ethyl-5'-methylaminouridine in 25 ml of drypyridine was stirred at 0° C. and treated with a solution of(2-bromophenyl)acetyl chloride (prepared from 0.65 g of the acid bytreatment with thionyl chloride in benzene under reflux) in 7 ml ofbenzene. The mixture was stirred at 0° C. for 0.5 hour and then storedat 4° C. overnight. The solvents were removed by evaporation and theresidue was re-evaporated with toluene to give a gum which wassubsequently triturated with diethyl ether to yield a solid. This solidwas taken up in 5 ml of methylene chloride/methanol (9:1) andchromatographed on a column of silica gel using methylenechloride/methanol (9:1) for the elution. The fractions containing theproduct were combined and evaporated. The residue was re-evaporated withethanol and recrystallized from methanol to give 0.18 g of5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine ofmelting point 182° -185° C.

In an analogous manner, from (2(RS)-(2,4-dichlorophenoxy)propionylchloride and 2',5'-dideoxy-5-ethyl-5'-methylaminouridine there wasobtained 5'-[2(RS)-(2,4-dichlorophenoxy)-N-methylpropionamido]-2',5'-dideoxy-5-ethyluridine of melting point 167°-177° C. (decomposition).

The 2',5'-dideoxy-5-ethyl-5'-methylaminouridine used above as thestarting material was prepared as follows:

26 g of 2'-deoxy-5-ethyluridine were dissolved in 400 ml of drypyridine. The solution was cooled to 0° C. and stirred while 20 g ofp-toluenesulfonyl chloride were added portionwise. Stirring at 0° C. wascontinued for 1 hour and the mixture was then left to stand at 4° C.overnight. The solvent was removed by evaporation and the residue wasre-evaporated with toluene. The residue was shaken with 200 ml ofmethanol and left to stand in a refrigerator for 2.5 hours to give asolid which was removed by filtration, washed with methanol and dried invacuo to give 18 g of crude product of melting point 183° C.(decomposition). Recrystallization from 450 ml of ethanol gave 13 g ofpure 2'-deoxy-5-ethyl-5'-O-(p-toluenesulfonyl)uridine of melting point189°-190° C. (decomposition).

1.8 g of the above product was dissolved in 10 ml of drydimethylformamide and 1.2 ml of N-benzylmethylamine were added. Themixture was stirred under nitrogen and heated at 80° C. for 5 hours. Thesolvent was removed by evaporation and the residue was re-evaporatedwith toluene. The residue was triturated with diethyl ether and removedby filtration to give 2.6 g of a solid of melting point 110°-115° C.This solid was taken up in 10 ml of methylene chloride/methanol (9:1)and chromatographed on a column of silica gel using methylenechloride/methanol (9:1) for the elution. The fractions containing theproduct were combined and evaporated. The residue was triturated withdiethyl ether to give 1.2 g of2',5'-dideoxy-5-ethyl-5'-(N-methyl-N-benzylamino)uridine of meltingpoint 135°-137° C.

1.1 g of 2',5'-dideoxy-5-ethyl-5'-(N-methyl-N-benzylamino)uridine weretaken up in 75 ml of ethanol and 1 g of 5% palladium-on-carbon catalystin 25 ml of ethanol was added under a nitrogen atmosphere. The mixturewas hydrogenated at room temperature and under atmospheric pressure. Thecatalyst was removed by filtration and the filtrate was evaporated togive 0.84 g of 2',5'-dideoxy-5-ethyl-5'-methylaminouridine of meltingpoint 145°-147° C.

EXAMPLE 18

In a manner analogous to that described in Example 17, there wasobtained:

(a) from (2,6-dichlorophenyl)acetyl chloride (prepared from 0.29 g ofthe acid by treatment with oxalyl chloride) and 0.35 g of2',5'-dideoxy-5-ethyl-5'-methylaminouridine there was obtained, afterchromatography and recrystallization from a mixture of 8 ml of ethanoland 24 ml of diethyl ether, 0.19 g of5'-[2-(2,6-dichlorophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridineof melting point 209°-210° C.

(b) from 2(RS)-(2-bromophenyl)propionyl chloride (prepared from 0.32 gof the acid by treatment with oxalyl chloride) and 0.35 g of2',5'-dideoxy-5-ethyl-5'-methylaminouridine there was obtained, afterchromatography on silica gel using methylene chloride/methanol (9:1) forthe elution, 0.19 g of5'-[2(RS)-(2-bromophenyl)-N-methylpropionamido]-2',5'-dideoxy-5-ethyluridineof melting point 80°-90° C. (decomposition).

EXAMPLE 19

0.05 g of5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridinewas dissolved in 2 ml of dry pyridine and the solution was treated with0.12 ml of acetic anhydride. The mixture was stirred at room temperaturefor 5 hours and then evaporated. The residue was re-evaporated withtoluene to give a solid which was triturated with diethyl ether and thenremoved by filtration. There was obtained 0.03 g of3'-O-acetyl-5'-[2-(2-bromophenyl)-N-methylacet-amido]-2',5'-dideoxy-5-ethyluridineof melting point about 170° C.

EXAMPLE 20

(A) 1.2 ml of a 1M sodium hydroxide solution was added to 0.255 g of5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water and then 0.21 gof naphthaloyl chloride was added. The mixture was shaken vigorously for10 minutes, whereby a white solid separated. This solid was collected byfiltration, washed three times with 5 ml of water each time and thendried in vacuo. Recrystallization from ethanol gave 0.2 g of2',5'-dideoxy-5-ethyl-5'-(2-naphthalamido)uridine in the form of a whitesolid of melting point 242°-244° C.

(B) In an analogous manner, there were prepared:

(a) from 5'-amino-2',5'-dideoxy-5-ethyluridine and 2-phenylbenzoylchloride:

2',5'-dideoxy-5-ethyl-5'-(2-phenylbenzamido)uridine, mp 246°-247° C.;

(b) from 5'-amino-2',5'-dideoxy-5-ethyluridine and 3-phenylpropionylchloride:

2',5'-dideoxy-5-ethyl-5'-(3-phenylpropionamido)uridine, mp 225°-226° C.;

(c) from 5'-amino-2',5'-dideoxy-5-ethyluridine and 4-phenylbutyrylchloride:

2',5'-dideoxy-5-ethyl-5'-(4-phenylbutyramido)uridine, mp 215° C.;

(d) from 5'-amino-2',5'-dideoxy-5-ethyluridine and cinnamoyl chloride:

2',5'-dideoxy-5'-cinnamamido-5-ethyluridine, mp 252°-254° C.;

(e) from 5'-amino-2',5'-dideoxy-5-ethyluridine and phenylpropiolylchloride:

2',5'-dideoxy-5-ethyl-5'-(3-phenyl-2-propynamido)uridine, mp 234°-236°C.;

(f) from 5'-amino-2',5'-dideoxy-5-ethyluridine and3-(phenylsulfonyl)propionyl chloride:

2',5'-dideoxy-5-ethyl-5'-[3-(phenylsulfonyl)propionamido]uridine, mp190°-192° C.; and

(g) from 5'-amino-2',5'-dideoxy-5-ethyluridine and 2-bromocinnamoylchloride:

5'-(2-bromocinnamamido)-2',5'-dideoxy-5-ethyluridine, mp 202°-204° C.

EXAMPLE 21

(A) 5 g of oxalyl chloride were added to a mixture of 5 g of2-thiopheneacetic acid and 1 drop of dimethylformamide in 40 ml of drybenzene. After stirring for 2 hours, the benzene was removed byevaporation and the crude 2-thiopheneacetyl chloride was purified bydistillation.

0.18 g of 2-thiopheneacetyl chloride was added to a solution of 0.255 gof 5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water containing 1.2of 1M sodium hydroxide solution and the resulting mixture was shakenvigorously for 10 minutes. The resulting white solid was collected byfiltration, washed with water, dried at 50° C. in vacuo over phosphoruspentoxide and recrystallized from ethanol to give 0.2 g of2',5'-dideoxy-5-ethyl-5'-[2-(2-thienyl)acetamido]ridine of melting point215°-217° C.

(B) In an analogous manner, there were obtained:

(a) from 5'-amino-2',5'-dideoxy-5-ethyluridine and 3-thiopheneacetic:

2',5'-dideoxy-5-ethyl-5'-[2-(3-thienyl)acetamido]uridine, mp 220°-222°C; and

(b) from 5'-amino-2',5'-dideoxy-5-ethyluridine and 1-adamantanecarbonylchloride:

5'-(1-adamantylcarboxamido)-2',5'-dideoxy-5-ethyluridine, mp 160°-162°C.

EXAMPLE 22

(A) A solution of 0.255 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in amixture of 5 ml of water and 1.1 ml of 1M sodium hydroxide solution wastreated with 0.14 g of picolinoyl chloride. The reaction mixture wasshaken vigorously for 15 minutes and the resulting dark brown solutionwas extracted twice with 10 ml of n-butanol each time. The extracts werewashed with saturated sodium chloride solution, dried over anhydroussodium sulfate and evaporated to give a buff colored solid. The solidwas purified by flash chromatography on a column of silica gel usingethyl acetate for the elution. Fractions containing the product werecombined and evaporated to give a light brown solid. Recrystallizationfrom ethanol/diethyl ether gave 0.12 g of2',5'-dideoxy-5-ethyl-5'-(2-pyridylcarboxamido)uridine in the form of awhite solid of melting point 196°-198° C.

(B) In an analogous manner, from 5'-amino-2',5'-dideoxy-5-ethyluridineand nicotinoyl chloride there was obtained2',5'-dideoxy-5-ethyl-5'-(3-pyridylcarboxamido)uridine of melting point223°-225° C.

EXAMPLE 23

A mixture of 0.26 g of 5'-amino-2',5'-dideoxy-5-ethyluridine 0.2 g ofphenylsulfonylacetic acid and 1.2 g of dicyclohexylcarbodiimide in 10 mlof dry pyridine was stirred overnight at room temperature. The solventwas removed by evaporation and the residue was re-evaporated three timeswith toluene and twice with diethyl ether. The residue was trituratedwith diethyl ether and left to stand at room temperature. The resultingsolid was removed by filtration, washed with diethyl ether and dried invacuo. The solid (0.66 g) was recrystallized from 15 ml of ethanol togive 0.40 g of product of melting point 213°-217° C. Furtherrecrystallization of 0.2 g of this product from 15 ml of ethanol gave0.09 g of 2',5'-dideoxy-5-ethyl-5'-[2-(phenylsulfonyl)acetamido]uridinein the form of a white solid of melting point 218°-219° C.

EXAMPLE 24

0.23 g of 9-fluorenecarboxylic acid was stirred in 10 ml of benzene at25° C. and treated with 0.15 g of oxalyl chloride and 1 drop ofdimethylformamide. The mixture was left to stand for 1.5 hours and wasthen evaporated. The residue was dissolved in 1.5 ml of benzene andadded to a solution of 0.26 g of 5'-amino-2',5'-dideoxy-5-ethyluridinein 5 ml of water and 1.5 ml of 1M sodium hydroxide solution. The mixturewas shaken vigorously for 15 minutes and then evaporated partially. Theresulting solid was removed by filtration and washed successively withwater, ethanol and diethyl ether to give 0.22 g of2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine of meltingpoint 275°-278° C. (decomposition).

EXAMPLE 25

A slurry of 0.45 g of2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine in 9 ml of drypyridine was stirred and treated with 0.6 ml of acetic anhydride. Themixture was stirred at room temperature for 4 hours and then left tostand overnight. The solvent was removed by evaporation and the residuewas re-evaporated with toluene. The residue was triturated with diethylether to give 0.4 g of crude product of melting point 240°-255° C.(decomposition). Recrystallization of the crude product from a mixtureof 10 ml of chloroform and 50 ml of diethyl ether gave 0.21 g of pure3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine ofmelting point 263°-265° C. (decomposition).

EXAMPLE 26

In a manner analogous to that described in Example 25, there areobtained:

(A) from 2.75 g of2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine and 1 ml ofbutyryl chloride there was obtained, after chromatography on silica gelusing methylene chloride/methanol (19:1) for the elution, 0.98 g of3'-O-butyryl-2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine ofmelting point 208°-210° C. (decomposition).

(B) from 0.45 g of2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine and 0.22 g oftert.butylacetyl chloride there was obtained, after chromatography onsilica gel using methylene chloride for the elution and trituration withpetroleum ether (b.p. 40°-60° C.), 0.14 g of2',5'-dideoxy-5-ethyl-3'-O-(3,3-dimethylbutyryl)-5'-(9-fluorenylcarboxamido)uridineof melting point 100°-110° C. (decomposition).

(C) from 0.45 g of2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine and 0.3 ofpalmitoyl chloride there was obtained, after recrystallization from amixture of 12 ml of ethyl acetate and 48 ml of petroleum ether (b.p.40°-60° C.), 0.14 g of2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)-3'-O-(hexadecanoyl)uridineof melting point 154°-157° C. (decomposition).

EXAMPLE 27

A slurry of 5.5 g of 9-fluorenecarboxylic acid in 100 ml of benzene wasstirred at 25° C. and there were then added 3.6 g of oxalyl chloridefollowed by 0.1 ml of dimethylformamide. The mixture was stirred for 1.5hours and then evaporated to give the acid chloride in the form of agum. This gum was cooled to -15° C. and treated with 90 ml of cold (-10°C.) pyridine. 3.3 g of 5'-amino-2',5'-dideoxy-5-ethyluridine were addedand the mixture was stirred at a temperature below 0° C. for 2.5 hoursto give a pale yellow solution which was left to stand at 4° C.overnight. The solvent was removed by evaporation and the residue wasre-evaporated with toluene. The residue was triturated with 70 ml ofwater to give a gum which, after trituration with 70 ml of ethanol, gave3.4 g of almost pure product of melting point 240°-245° C.(decomposition). Recrystallization from a mixture of 110 ml of methylenechloride and 110 ml of diethyl ether gave 2.3 g of pure2',5'-dideoxy-5-ethyl-3'-O-(9-fluorenylcarbonyl)-5'-(9-fluorenylcarboxamido)uridineof melting point 240°-245° C. (decomposition).

EXAMPLE 28

(A) 1.25 of 1M sodium hydroxide solution were added to 0.255 g of5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water and then 0.2 g of2-phenylbutyryl chloride was added to the mixture. The resulting mixturewas shaken for 10 minutes, whereby a white solid was deposited. Thissolid was collected by filtration, washed three times with 5 ml of watereach time, dried at 50° C. in vacuo over phosphorus pentoxide andrecrystallized from ethanol to give 0.28 g of2',5'-dideoxy-5-ethyl-5'-(2-phenylbutyramido)uridine of melting point235°-236° C.

(B) In an analogous manner, there were obtained:

(a) from 5'-amino-2',5'-dideoxy-5-ethyluridine and 3-phenylbutyrylchloride:

2',5'dideoxy-5-ethyl-5'-(3-phenylbutyramido)uridine, mp 222°-223° C.;

(b) from 5'-amino-2',5'-dideoxy-5-ethyluridine and diphenylacetylchloride:

2',5'-dideoxy-5-ethyl-5'-(2,2-diphenylacetamido)uridine, mp 208°-210°C.; and

(c) from 5'-amino-2',5'-dideoxy-5-ethyluridine andcyclohexylphenylacetyl chloride:

5'-(2-cyclohexyl-2-phenylacetamido)-2',5'-dideoxy-5-ethyluridine ofmelting point 130°-132° C.

EXAMPLE 29

A slurry of 0.4 g of triphenylacetic acid in 10 ml of benzene wasstirred at 25° C. and treated with 0.2 g of oxalyl chloride and 1 dropof dimethylformamide. Effervesence occurred over a period of about 30minutes, after which time a solution was obtained. This solution wasleft to stand at room temperature for 1.5 hours and was then evaporatedto give triphenylacetyl chloride in the form of an oil. The acidchloride was cooled to about -10° C. by means of an ice/salt bath and 10ml of dry pyridine and 0.36 g of 5'-amino-2',5'-dideoxy-5-ethyluridinewere added. The mixture was shaken for about 15 minutes, whereby theacid chloride dissolved and the temperature rose to 0° C. The solutionwas then stirred at 0° C. for 4 hours and then evaporated. The residuewas re-evaporated three times with toluene, there being obtained a gumwhich was triturated with 20 ml of water to give 0.66 g of a solid ofmelting point 110°-140° C. Recrystallization from 12 ml of ethanolremoved residual triphenylacetic acid and the residue waschromatographed on a column of silica gel using methylenechloride/methanol (9:1) for the elution. Recrystallization from amixture of 5 ml of toluene, 10 ml of cyclohexane and 0.1 ml of ethylacetate gave 0.25 g of2',5'-dideoxy-5-ethyl-5'-(triphenylacetamido)uridine of melting pointabout 110°-120° C. (decomposition).

EXAMPLE 30

In a manner analogous to that described in Example 29, from 0.66 g of2-phenylisobutyric acid and 0.89 g of5'-amino-2',5'-dideoxy-5-ethyluridine there was obtained, afterchromatography and trituration with diethyl ether, 0.23 g of2',5'-dideoxy-5-ethyl-5'-(2-methyl-2-phenylpropionamido)uridine ofmelting point 156°-158° C.

EXAMPLE 31

In a manner analogous to that described in Example 29, but using thionylchloride to produce the acid chloride, from 0.55 ml of2(RS)-phenylpropionic acid and 0.89 g of5'-amino-2',5'-dideoxy-5-ethyluridine there was obtained, afterrecrystallization from ethanol, 0.59 g of2',5'-dideoxy-5-ethyl-5'-[2(RS)-phenylpropionamido)]uridine of meltingpoint 237°-239° C.

EXAMPLE 32

(A) A suspension of 2.35 g of 2(RS)-(2,4-dichlorophenoxy)propionic acidin a mixture of 50 ml of benzene, 20 ml of oxalyl chloride and 0.1 mldimethylformamide was stirred at room temperature for 1.5 hours. Themixture was evaporated to dryness and a solution of the residue in 50 mlof diethyl ether was added to a solution of 2.55 g of5'-amino-2',5'-dideoxy-5-ethyluridine in 40 ml of 0.25M sodium hydroxidesolution. The mixture was shaken vigorously for 10 minutes and thenfiltered. The solid was washed with 100 ml of water and with 50 ml ofdiethyl ether and recrystallized from 1 l of ethanol to give 2.31 g of5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridinein the form of a white solid of melting point 240°-243° C.

(B) In an analogous manner, there were obtained:

(1) from 2(RS)-(2,6-dichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2,6-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 206° C.;

(2) from 2(RS)-(3,5-dichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(3,5-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 224°-226° C.;

(3) from 2(RS)-(2-chlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2-chlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 204°-206° C.;

(4) from 2-(2,6-dichlorophenoxy)acetic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2-(2,6-dichlorophenoxy)acetamido]-2',5'-dideoxy-5-ethyluridine, mpof 193.5°-194° C.;

(5) from 2-(2,4-dichlorophenoxy)acetic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2-(2,4-dichlorophenoxy)acetamido]-2',5'-dideoxy-5-ethyluridine, mp191°-193° C.;

(6) from 4-(2,6-dichlorophenoxy)butanoic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[4-(2,6-dichlorophenoxy)butyramido]-2',5'-dideoxy-5-ethyluridine, mp218°-220° C.;

(7) from 6-(2,6-dichlorophenoxy)hexanoic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[6-(2,6-dichlorophenoxy)hexanamido]-2',5'-dideoxy-5-ethyluridine, mp219°-221° C.;

(8) from 5-(2,6-dichlorophenoxy)pentanoic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[5-(2,6-dichlorophenoxy)valeramido]-2',5'-dideoxy-5-ethyluridine, mp215°-217° C.;

(9) from 3-(2,6-dichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[3-(2,6-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 217°-218° C.;

(10) from [2(RS)-(2-chloro-4-nitrophenoxy)]propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2-chloro-4-nitrophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 214°-216° C.;

(11) from [2(RS)-(2-chloro-4-phenylphenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2-chloro-4-phenylphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 219°-228° C.;

(12) from 2(R)-(2,4-dichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(R)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 230°-231° C.;

(13) from 2(S)-(2,4-dichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(S)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 260.5°-261.5° C.;

(14) from (2(RS)-(2,4,5-trichlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 255°-257° C.;

(15) from 2(RS)-(2,4-dichlorophenoxy)butyric acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2,4-dichlorophenoxy)butyramido]-2',5'-dideoxy-5-ethyluridine,mp 223°-227° C.;

(16) from 2(RS)-(4-chloro-2-nitrophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(4-chloro-2-nitrophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 199°-201° C.;

(17) from 2(RS)-(4-acetamido-2-chlorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(4-acetamido-2-chlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 234°-236° C.;

(18) from 2(RS)-(2,4-dichlorophenoxy)-2-phenylacetic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2,4-dichlorophenoxy)-2-phenylacetamido]-2',5'-dideoxy-5-ethyluridine,mp 120°-125° C.;

(19) from 2(RS)-(2,4-dichloro-5-methoxyphenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2,4-dichloro-5-methoxyphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 191°-194° C.;

(20) from 2(RS)-(2-chloro-4-methoxyphenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2(RS)-(2-chloro-4-methoxyphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 215°-221° C.;

(21) from 2(RS)-(2-methylbiphenylyloxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-methylbiphenylyloxy)propionamido]uridine,mp 216°-217° C.;

(22) from 2(RS)-(2,4-dichlorophenoxy)propionic acid and5'-amino-5'-deoxythymidine:

5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-5'-deoxythymidine, mp208°-210° C.;

(23) from 2-(2,4-dichlorophenoxy)-2-methylpropionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

5'-[2-(2,4-dichlorophenoxy)-2-methylpropionamido]-2',5'-dideoxy-5-ethyluridine,mp 188°-190° C.;

(24) from 2(RS)-phenoxypropionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

2',5'-dideoxy-5'-[2(RS)-phenoxypropionamido]uridine, mp 214°-216° C.;

(25) from 2(RS)-(2-fluorophenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-fluorophenoxy)propionamido]uridine,mp 205°-207° C.;

(26) from 2(RS)-(2-trifluoromethylphenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-trifluoromethylphenoxy)propionamido]uridine,mp 221°-225° C.; and

(27) from 2(RS)-(2-phenylphenoxy)propionic acid and5'-amino-2',5'-dideoxy-5-ethyluridine:

2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-phenylphenoxy)propionamido]uridine,mp 206°-207° C.

The 4-(2,6-dichlorophenoxy)butanoic acid referred to earlier wasprepared as follows:

Small pieces of sodium (353 mg) were added to a stirred solution of 2.5g of 2,6-dichlorophenol in 10 ml of ethanol and the mixture was stirredat room temperature until the evolution of gas had ceased. 2.715 g ofmethyl 4-bromobutyrate were added and the mixture was stirred and heatedunder reflux for 4 hours. After cooling the mixture was filtered and thefiltrate was evaporated to dryness. The residue was dissolved in 50 mlof dichloromethane and the solution was washed with 10% sodium carbonatesolution, dried over anhydrous sodium sulfate and evaporated to give3.62 g of a colorless oil.

The above oil was dissolved in 20 ml of ethanol and the solution wastreated with a solution of 0.5 g of potassium hydroxide in 10 ml ofwater. The mixture was stirred and heated under reflux for 3 hours andthen evaporated to dryness. The residue was taken up in 50 ml ofsaturated sodium hydrogen carbonate solution and the resulting solutionwas washed twice with 50 ml of dichloromethane each time, acidified with2M hydrochloric acid and extracted with 50 ml of dichloromethane. Thedichloromethane extract was dried over anhydrous sodium sulfate andevaporated to give 1.3 g of 4-(2,6-dichlorophenoxy)butanoic acid in theform of a white crystalline solid of melting point 68°-67° C.

In an analogous manner,

from 2,6-dichlorophenol and methyl 6-bromohexanoate there was obtained6-(2,6-dichlorophenoxy)hexanoic acid; and

from 2,6-dichlorophenol and methyl 5-bromopentanoate there was obtained5-(2,6-dichlorophenoxy)pentanoic acid.

EXAMPLE 33

In a manner analogous to that described in Example 32, from2(RS)-(2,4-dichlorophenoxy)propionic acid and1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracilthere was obtained1-[5-[2-(RS)-(2,4-dichlorophenoxy)propionamido]-2,5-dideoxy-2-fluoro-.beta.-D-arabinofuranosyl]-5-ethyluracilof melting point 194°-214° C.

The 1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracilused above as the starting material was prepared as follows:

A mixture of 0.4 g of1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil, 0.44 g oftriphenylphosphine, 0.48 g of sodium azide and 6 ml of drydimethylformamide was stirred at room temperature under nitrogen while0.48 g of carbon tetrabromide was added portionwise. The mixture wasstirred at room temperature under nitrogen for 20 hours. 3 ml ofmethanol were added, the mixture was stirred for 0.5 hour and thenevaporated. The residue was stirred for 0.5 hour with 8 ml of 0.5Msodium hydroxide solution. The resulting suspension was filtered and theinsoluble triphenylphosphine oxide was washed with water. The filtratewas acidified to pH 5 by the addition of hydrochloric acid and thenextracted three times with 20 ml of ethyl acetate. The extracts weredried over magnesium sulfate, filtered and evaporated. The residualsolid was washed on to a filter with 10 ml of diethyl ether/petroleumether (1:1) and then dried in vacuo to give 0.4 g of 1-(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as awhite solid of melting point 185°-188° C.

A solution of 0.4 g of1-(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil in20 ml of ethanol was hydrogenated at room temperature and underatmospheric pressure in the presence of 0.1 g of 10% palladium-on-carboncatalyst for 24 hours. The catalyst was removed by filtration and thefiltrate was evaporated. The residue was triturated with diethyl etherand the solid was removed by filtration, washed with ethyl acetate anddried in vacuo to give 0.3 g of1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as awhite solid.

EXAMPLE 34

In a manner analogous to that described in Example 32, from2(RS)-(2,4-dichlorophenoxy)propionic acid and1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)thymine there wasobtained1-[5-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]thymidineof melting point 147°-155° C.

The 1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)thymine used asthe starting material was prepared from1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)thymine in a manner analogousto that described in Example 33 for the preparation of1-(5-amino-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil.

EXAMPLE 35

A suspension of 3.0 g of 2(RS)-(2,4-dichlorophenylthio)propionic acid ina mixture of 50 ml of toluene, 5 ml of oxalyl chloride and 0.1 ml ofdimethylformamide was stirred at room temperature for 2.5 hours. Themixture was evaporated to dryness and a solution of the residue in 20 mlof diethyl ether was added to a solution of 3.05 g of5'-amino-2',5'-dideoxy-5-ethyluridine in 32 ml of 0.375M sodiumhydroxide solution. The mixture was shaken vigorously for 5 minutes andthen filtered. The solid was washed with water and recrystallized from600 ml of ethanol to give 3.0 g of5'-[2(RS)-(2,4-dichlorophenylthio)propionamido]-2',5'-dideoxy-5-ethyluridinein the form of a pale yellow solid of melting pont 218°-220° C.

The 2(RS)-(2,4-dichlorophenythio)propionic acid used as the startingmaterial was prepared as follows:

A mixture of 11.78 g of 2,4-dichlorothiophenol and 12.0 g of potassiumhydroxide in 50 ml of acetone was stirred and heated to reflux. 11.77 gof ethyl 2-bromopropionate were added gradually and the mixture washeated under reflux for 22 hours. After cooling to room temperature, themixture was filtered and the filtrate was evaporated to dryness. Theresidue was taken up in 400 ml of diethyl ether and the solution waswashed with 400 ml of water and 400 ml of 10% sodium carbonate solution,dried over anhydrous sodium sulfate and evaporated to dryness. Asolution of the residue in a mixture of 30 ml of ethanol and 17 ml of10% potassium hydroxide solution was heated under reflux for 21 hours.The solution was evaporated to dryness and the residue was dissolved in50 ml of water. The resulting solution was washed twice with 50 ml ofdiethyl ether each time and then acidified with concentratedhydrochloric acid and extracted twice with 150 ml of ethyl acetate eachtime. The combined organic extracts were washed twice with 200 ml ofwater each time, dried over anhydrous sodium sulfate and evaporated todryness. The residue was recrystallized from diethyl ether to give 4.08g of 2(RS)-(2,4-dichlorophenyl-thio)propionic acid in the form of ayellow solid of melting point 95°-98° C.

EXAMPLE 36

A suspension of 250 mg of5'-[2(RS)-(2,4-dichlorophenylthio)propionamido]-2',5'-dideoxy-5-ethyluridinein 10 ml of acetic acid was cooled to 0° C. and 60 mg of 30% hydrogenperoxide were added. The mixture was stirred at 0° C. for 0.5 hour andthen at room temperature overnight. An additional 60 mg of 30% hydrogenperoxide were added and the mixture was stirred for 24 hours. Anadditional 30 mg of 30% hydrogen peroxide were added and the mixture wasstirred for an additional 4 hours and then evaporated to dryness. Theresidue was triturated with methanol and the resulting solid was removedby filtration and recrystallized from methanol to give 90 mg of5'-[2(RS)-(2,4-dichlorophenylsulphinyl)propionamido]-2',5'-dideoxy-5-ethyluridinein the form of a white solid of melting point 208°-209° C.

EXAMPLE 37

A suspension of 250 mg of5'-[2(RS)-(2,4-dichlorophenylthio)propionamido]-2',5'-dideoxy-5-ethyluridinein 10 ml of acetic acid was cooled to 0° C. and 800 mg of 30% hydrogenperoxide were added. The mixture was stirred at 0° C. for 0.5 hour andthen at room temperature overnight. The mixture was evaporated todryness and the residue was recrystallized from methanol to give 140 mgof5'-[2(RS)-(2,4-dichlorophenylsulfonyl)propionamido]-2',5'-dideoxy-5-ethyluridinein the form of a white solid of melting point 183°-184° C.

EXAMPLE 38

(A) A suspension of 51 mg of 2,6-dichlorophenylacetic acid in a mixtureof 10 ml of toluene, 100 mg of oxalyl chloride and 1 drop ofdimethylformamide was stirred at room temperature for 0.5 hour. Themixture was evaporated to dryness and a solution of the residue in 2 mlof diethyl ether was added to a solution of 70 mg of5'-(2-aminoethyl)-2',5'-dideoxy-5-ethyluridine in 5 ml of 0.1M sodiumhydroxide solution. The mixture was shaken vigorously for 5 minutes andthen filtered. The solid was washed in succession with water, ethanoland diethyl ether and then dried over anhydrous sodium sulfate to give90 mg of5'-[2-(2,6-dichlorophenylacetamido)ethyl]-2',5'-dideoxy-5-ethyluridinein the form of a white solid of melting point 227°-229° C.

(B) In an analogous manner, there were obtained:

(a) from 5'-[2-(aminoethyl)]-2',5'-dideoxy-5-ethyluridine and2(RS)-(2,4,5-trichlorophenoxy)propionic acid:

5'-[2-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]ethyl]-2',5'-dideoxy-5-ethyluridine,mp 184°-185° C.; and

(b) from 5'-[2-(aminoethyl)]-2',5'-dideoxy-5-ethyluridine and2(RS)-(2,4-dichlorophenoxy)propionic acid:

5'-[2-[2(RS)-(2,4-dichlorophenoxy)propionamido]ethyl]-2',5'-dideoxy-5-ethyluridineof melting point 170°-172° C.

The 5'-(2-aminoethyl)-2',5'-dideoxy-5-ethyluridine used above as thestarting material was prepared as follows:

1.9 g of dichloroacetic acid were added to a mixture of 8.95 g of3'-O-acetyl-2',5'-dideoxy-5-ethyluridine and 18.6 g ofdicyclohexylcarbodiimide in 75 ml of dimethyl sulfoxide. The mixture wasstirred at room temperature for 24 hours. 1.2 ml of pyridine and 10.5 gof carbethoxymethylenetriphenylphosphorane were added and the mixturewas stirred at room temperature for an additional 24 hours. The solventwas removed in vacuo and the residue was dissolved in 300 ml of ethylacetate. The solution was washed with 300 ml of water, dried overanhydrous sodium sulfate and evaporated to give a yellow oil. This oilwas subjected to flash chromatography on a column of silica gel using 5%methanol/dichloromethane for the elution. The product was recrystallizedfrom ethanol to give 7.3 g oftrans-3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethylene)-5-ethyluridinein the form of a white solid of melting point 132°-133° C.

A solution of 7.3 g oftrans-3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethylene)-5-ethyluridinein 150 ml of ethanol was hydrogenated over 0.5 g of 10%palladium-on-carbon catalyst for 6 hours. The catalyst was removed byfiltration and the filtrate was evaporated to dryness. The residue wasrecrystallized from ethanol to give 5.8 g of3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethyl)-5-ethyluridine inthe form of a white solid of melting point 137°-138° C.

0.4 g of lithium borohydride was added to a solution of 5.6 g of3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethyl)-5-ethyluridine in100 ml of tetrahydrofuran and the mixture was stirred at roomtemperature for 4 hours. An additional 0.2 g of lithium borohydride wasadded and the mixture was stirred at room temperature overnight and thenheated under reflux for 1 hour. The solvent was removed by evaporationin vacuo and the residue was dissolved in methanol. After standing atroom temperature for a few minutes, the solvent was removed byevaporation and the residue was taken up in 40 ml of pyridine. 5 g ofacetic anhydride were added and the mixture was stirred at roomtemperature overnight. Pyridine was removed by evaporation and theresidue was partitioned between water and ethyl acetate. The aqueoussolution was evaporated to dryness and the residue was subjected toflash chromatography on a column of silica gel using 10%methanol/dichloromethane for the elution to give 1.3 g of5'-(2-acetoxyethyl)- 3'-O-acetyl-2',5'-dideoxy-5-ethyluridine in theform of a colorless oil which crystallized upon standing.

0.10 g of 5'-(2-acetoxyethyl)-3'-O-acetyl-2',5'-dideoxy-5-ethyluridinewas treated with 5 ml of a dilute solution of sodium methoxide inmethanol. After standing at room temperature for 2 hours the solutionwas neutralized by the addition of a cross-linkedpolystyrene-divinylbenzene cation exchange resin containing sulfonicacid groups (H⁺ form) and then filtered. The filtrate was evaporated todryness to give 0.045 g of2',5'-dideoxy-5-ethyl-5'-(2-hydroxyethyl)uridine in the form of a whitesolid of melting point 113°-115° C.

A mixture of 1.25 g of 2',5'-dideoxy-5-ethyl-5'-(2-hydroxyethyl)uridine,1.18 g of triphenylphosphine, 1.49 g of sodium azide and 1.55 g ofcarbon tetrabromide in 30 ml of dimethylformamide was stirred at roomtemperature overnight. The mixture was evaporated to dryness and theresidue was partitioned between ethyl acetate and water. The ethylacetate solution was evaporated to dryness and the residue was subjectedto flash chromatography on a column of silica gel using 1%methanol/dichloromethane for the elution to give 0.28 g of5'-(2-azidoethyl)-2',5'-dideoxy-5-ethyluridine in the form of acolorless oil which crystallized upon standing.

A solution of 0.28 of 5'-(2-azidoethyl)-2',5'-dideoxy-5-ethyluridine in50 ml of ethanol was hydrogenated over 50 mg of 10% palladium-on-carboncatalyst for 2 hours. The catalyst was removed by filtration and thefiltrate was evaporated to dryness to give 0.23 g of5'-(2-aminoethyl)-2',5'-dideoxy-5-ethyluridine in the form of acolorless oil which crystallized upon standing.

EXAMPLE 39

0.175 g of 2(RS)-(2,6-dichlorobenzyl)propionic acid was dissolved in 5ml of dry benzene containing 1 drop of dimethylformamide. 96 mg ofoxalyl chloride were then added. After 1 hour the solvent was removed byevaporation. The residue was treated with a solution of5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of an aqueous solutioncontaining 3 ml of 2M sodium hydroxide solution. The mixture was shakenfor 15 minutes. The resulting precipitate was removed by filtration,dried over anhydrous sodium sulfate and recrystallized from a mixture ofethanol and diethyl ether to give 0.11 g of5'-[2(RS)-(2,6-dichlorobenzyl)propionamido]-2',5'-dideoxy-5-ethyluridineof melting point 194°-197° C.

The 2(RS)-(2,6-dichlorobenzyl)propionic acid used as the startingmaterial was prepared as follows:

2.4 g of triethyl 2-phosphinopropionate and 1.75 g of2,6-dichlorobenzaldehyde were dissolved in 15 ml of drydimethylformamide. 0.29 g of a 80% dispersion of sodium hydride inmineral oil was added portionwise and the mixture was stirred for 2hours. 100 ml of water were added and the mixture was extracted threetimes with 40 ml of methylene chloride each time. The combined methylenechloride extracts were back-washed twice with 50 ml of sodium chloridesolution each time and the solvent was removed by evaporation to give2.4 g of ethyl 2,6-dichloro-2-methylcinnamate in the form of an oil.

0.26 g of ethyl 2,6-dichloro-2-methylcinnamate were dissolved in 10 mlof methanol and the solution was treated with 0.96 g of magnesiumturnings and stirred. The mixture was cooled to -5° C. to 0° C. in anice-salt bath and maintained at this temperature for 1 hour. The mixturewas then held at room temperature for 4 hours. 25 ml of 6M hydrochloricacid were added dropwise during 20 minutes to give a clear solution. Thesolution was extracted three times with 15 ml of diethyl ether each timeand the combined extracts were dried over anhydrous sodium sulfate andevaporated to give 0.21 g of a colorless oil which, according to nmrspectroscopy, was a 2:1 mixture of methyl and ethyl2(RS)-(2,6-dichlorobenzyl)propionate.

0.20 g of the above mixture was dissolved in a mixture of 5 ml of 10%potassium hydroxide solution and 5 ml of ethanol. The solution washeated under reflux for `hours. The ethanol was removed by evaporationand the residue was cooled and acidified with concentrated hydrochloricacid. Extraction with three 10 ml portions of ethyl acetate, washingwith sodium chloride solution, drying over anhydrous sodium sulfate andevaporation of the solvent gave 0.18 g of2(RS)-(2,6-dichlorobenzyl)propionic acid as an oil.

EXAMPLE 40

In a manner analogous to that described in Example 39, there wereobtained:

(A) from 0.21 g of 2(RS)-(2,4-dichlorobenzyl)propionic acid and 0.20 gof 5'-amino-2',5'-dideoxy-5-ethyluridine:

0.35 g of5'-[2(RS)-(2,4-dichlorobenzyl)propionamido]-2',5'-dideoxy-5-ethyluridine,mp 243°-245° C.

(B) from 0.20 g of 5-chloro-2,3-dihydro-2(RS)-benzofurancarboxylic acidand 0.26 g of 5'-amino-2',5'-dideoxy-5-ethyluridine:

0.10 g of5'-[5-chloro-2,3-dihydro-2(RS)-benzofuranylcarboxamido]-2',5'-dideoxy-5-ethyluridine,mp 204°-206° C.

(C) from 0.10 g of 6-chlorochroman-2-carboxylic acid and 0.12 g of5'-amino-2',5'-dideoxy-5-ethyluridine:

20 mg of5-(6-chloro-2H-1-benzopyran-2-ylcarboxamido)-5'-dideoxy-5-ethyluridine,mp 171°-176° C.

EXAMPLE 41

In a manner analogous to that described in Example 15, from 0.335 g of2-(4-benzyloxy-2,6-dimethylphenyl)acetic acid and 0.28 g of5'-amino-2',5'-dideoxy-5-ethyluridine there was obtained, afterrecrystallization from a mixture of 2-methoxyethanol and water, 0.33 gof5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridineof melting point 259°-260° C.

The 2-(4-benzyloxy-2,6-dimethylphenyl)acetic acid used as the startingmaterial was prepared as follows:

0.36 g of 2-(4-hydroxy-2,6-dimethylphenyl)acetic acid was treated with184 mg of a 60% dispersion of sodium hydride in mineral oil and 0.72 gof benzyl bromide in 10 ml of dry dimethylformamide. The solvent wasremoved by evaporation and the residue was partitioned between water andmethylene chloride. The organic layer was evaporated to give 0.63 g ofcrude product of melting point 54°-57° C. Recrystallization from aqueousmethanol gave 0.58 g of pure benzyl2-(4-benzyloxy-2,6-dimethylphenyl)acetate of melting point 62°-64° C.

0.35 g of benzyl 2-(4-benzyloxy-2,6-dimethylphenyl)acetate was shakenovernight with a mixture of 7 ml of methanol, 0.7 ml of water and 0.28 gof solid sodium hydroxide. The resulting solution was evaporated and theresidue was partitioned between 50 ml of methylene chloride and 25 ml of2M hydrochloric acid. The organic layer was dried over anhydrous sodiumsulfate and evaporated. The solid residue was recrystallized from amixture of 3 ml of methanol and 3 ml of water to give 0.21 g of2-(4-benzyloxy-2,6-dimethylphenyl)acetic acid of melting point 149°-150°C.

EXAMPLE 42

0.25 g of5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridinewas stirred as a slurry in 5 ml of dry pyridine with 0.4 ml of aceticanhydride for 72 hours. The resulting solution was evaporated in vacuoand the residue was re-evaporated three times with toluene. Aftertrituration with diethyl ether and filtration there was obtained 0.22 gof crude product of melting point 188°-191° C. Recrystallization from amixture of 4 ml of methylene chloride and 4 ml of petroleum ether gave0.20 g of pure3'-O-acetyl-5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridineof melting point 194°-196° C. (dec).

EXAMPLE 43

0.165 g of3'-O-acetyl-5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridinewas dissolved in 25 ml of methanol. A slurry of 0.1 g of 5%palladium-on-charcoal catalyst in ethanol was added. The mixture washydrogenated at room temperature and under atmospheric pressure for 2hours. The catalyst was removed by filtration and the filtrate wasevaporated to give 0.125 g of solid of melting point 234°-237° C.Recrystallization from a mixture of 10 ml of acetone and 20 ml ofpetroleum ether gave 80 mg of3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridineof melting point 240°-241° C. (dec).

EXAMPLE 44

24 mg of5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridinewere dissolved in 50 ml of methanol and the solution was hydrogenatedover 15 mg of 5% palladium-on-charcoal catalyst at room temperature andunder atmospheric pressure for 72 hours. The catalyst was removed byfiltration and the filtrate was evaporated to give 15 mg of2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridineof melting point 221°-225° C. (decomposition).

EXAMPLE 45

95 mg of3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridinewere dissolved in 5 ml of dry dimethylformamide while stirringmagnetically at room temperature. 69 mg of a 60% dispersion of sodiumhydride in mineral oil were added and the mixture was stirred for 1hour. 68 mg of freshly prepared dibenzylphosphoryl chloride in 2 ml ofdry benzene were added and the mixture was stirred at room temperaturefor 18 hours. The mixture was poured into 30 ml of saturated aqueoussodium bicarbonate solution and the product was extracted with ethylacetate. The extract was evaporated to give an oil which was purified byflash chromatography on silica gel using 5% methanol/dichloromethane forthe elution. The solvent was removed by evaporation to give 65 mg ofproduct which, after trituration with petroleum ether (boiling point60°-80° C.), gave3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[2-(2,6-dimethyl-4-(dibenzyloxyphosphinyloxy)phenyl]acetamido]uridine in the form of awhite crystalline solid.

The above solid was taken up in 10 ml of a saturated solution of ammoniain methanol at room temperature and left to stand overnight. The solventwas removed by evaporation to give2',5'-dideoxy-5-ethyl-5'-[2-[2,6-dimethyl-4-(dibenzyloxyphosphinyloxy)phenyl]acetamido]uridinein the form of a solid.

60 mg of the above solid were suspended in 10 ml of ethanol. 10 mg of10% palladium-on-charcoal catalyst were added and the mixture washydrogenated at room temperature and under atmospheric pressure for 4hours. The catalyst was removed by filtration and washed with severalportions of warm ethanol. The combined filtrates were evaporated to give40 mg of2',5'-dideoxy-5-ethyl-5'-[2-(2,6-dimethyl-4-phosphatophenyl)acetamido]uridineof melting point 214°-216° C.

EXAMPLE 46

(A) In a manner analogous to that described in Example 16, from 0.22 gof (RS)-(2,4-dichlorophenoxy)propionic acid and 0.27 g of5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride there wasobtained, after recrystallization from a mixture of 2-methoxyethanol andwater, 0.13 g of5-(2-chloroethyl)-2',5'-dideoxy-5'-[2-(2,4-dichlorophenoxy)propionamido]uridineof melting point 214°-216° C.,

(B) from 55 mg of benzoyl chloride and 115 mg of5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride there wereobtained, after recrystallization from a mixture of 2-methoxyethanol andwater, 70 mg of 5'-benzamido-5-(2-chloroethyl)-2',5'-dideoxyuridine ofmelting point 249°-250° C. (decomposition),

(C) from 104 mg of 2-(2,4,5-trichlorophenoxy)propionic acid and 115 mgof 5'-amino-5-(2-chloroethyl)-2',5'-dideoxyuridine hydrochloride therewere obtained, after recrystallization from a mixture of2-methoxyethanol and water, 95 mg of5-(2-chloroethyl)-5-[2-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxyuridineof melting point 223°-225° C.,

(D) from 136 mg of 2,6-dichlorophenylacetic acid and 0.16 g of5'-amino-2',5'-dideoxy-5-n-propyluridine there was obtained, afterrecrystallization from a mixture of 2-methoxyethanol and water, 0.21 gof 5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-propyluridine ofmelting point 297°-298° C. (decomposition).

The 5'-amino-2',5'-dideoxy-5-n-propyluridine used as the startingmaterial was prepared as follows:

0.57 g of 2'-deoxy-5-n-propyluridine, 0.6 g of triphenylphosphine and0.69 g of sodium azide were stirred in 20 ml of dry dimethylformamide.0.77 g of carbon tetrabromide was added over a period of 5 minutes. Themixture was stirred at room temperature for 72 hours, 20 ml of methanolwere added and the mixture was stirred for a further 0.5 hour. Themixture was evaporated and the residue was stirred with a mixture of 25ml of dichloromethane/methanol (8:2). An insoluble solid was removed byfiltration and the filtrate was chromatographed on 200 g of silica gelin the same solvent mixture to give 0.41 g of5'-azido-2',5'-dideoxy-5-n-propyluridine of melting point 177°-179° C.(decomposition).

0.38 g of 5'-azido-2',5'-dideoxy-5-n-propyluridine was dissolved in 100ml of ethanol and the solution was hydrogenated in the presence of 0.1 gof 10% palladium-on-charcoal catalyst for 2 hours at room temperatureand under atmospheric pressure. The catalyst was removed by filtrationand the filtrate was evaporated to give5'-amino-2',5'-dideoxy-5-n-propyluridine in the form of a solid whichwas used without further purification.

EXAMPLE 47

In a manner analogous to that described in Example 46D, from 155 mg of2(RS)-(2,4-dichlorophenoxy)propionic acid and 0.16 g of5'-amino-2',5'-dideoxy-5-n-propyluridine there was obtained 0.20 g of5-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-propyluridineof melting point 232°-243° C. (decomposition).

EXAMPLE 48

In a manner analogous to that described in Example 16, from 0.23 g of2,6-dichlorophenylacetic acid and 0.31 g of5-acetyl-5'-amino-2',5'-dideoxyuridine hydrochloride there wereobtained, after recrystallization from a mixture of ethanol andpetroleum ether, 60 mg of5-acetyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine ofmelting point 210°-212° C. (dec.).

The 5-acetyl-5'-amino-2',5'-dideoxyuridine hydrochloride used as thestarting material was prepared as follows:

1.26 g of 5-acetyl-2'-deoxyuridine, 1.35 g of triphenylphosphine, 1.52 gof sodium azide and 1.7 g of carbon tetrabromide in 40 ml ofdimethylformamide were reacted as described in Example 54 and theproduct was purified by chromatography on 400 g of silica gel indichloromethane/methanol (9:1) to give 0.80 g of5-acetyl-5'-azido-2',5'-dideoxyuridine of melting point 159°-162° C.(decomposition).

0.80 g of 5-acetyl-5'-azido-2',5'-dideoxyuridine was dissolved in 100 mlof methanol and 10 ml of 0.27M hydrogen chloride in methanol were added.0.1 g of 5% palladium-on-charcoal catalyst was added as a slurry inethanol and the mixture was hydrogenated for 3 hours at room temperatureand under atmospheric pressure. The catalyst was removed by filtrationand the filtrate was evaporated to give 0.91 g of hygro-scopic5-acetyl-5'-amino-2',5'-dideoxyuridine hydrochloride of melting point73°-85° C. (decomposition).

The following Example illustrates a pharmaceutical preparationcontaining a compound of formula I:

Tablets may contain the following ingredients:

    ______________________________________                                        Ingredient             Per tablet                                             ______________________________________                                        Compound of formula I  100    mg                                              Lactose                70     mg                                              Maize starch           70     mg                                              Polyvinylpyrrolidone   5      mg                                              Magnesium stearate     5      mg                                              Tablet weight          250    mg                                              ______________________________________                                    

We claim:
 1. A compound of the formula ##STR5## wherein R¹ is halogen,C₁₋₄ -alkyl, halo-(C₁₋₄ -alkyl) or C₂₋₄ -alkanoyl,R² is hydrogen,hydroxy, C₁₋₄ -alkoxy-C₁₋₄ -alkylthio phenyl-(C₁₋₄ -alkoxy) or C₂₋₄-alkanoyloxy, R³ is hydrogen or C₁₋₄ -alkyl, R⁴ is a carbocyclic groupselected from the group consisting of 2-biphenylyl, 4-biphenylyl,3-chloro-4-biphenylyl, 1-naphthyl, 2-naphthyl, cyclopentyl, cyclohexyl,adamantyl, indanyl, fluorenyl and phenyl which may be substituted by oneor more substituents selected from the group consisting of halogen,hydroxy, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, trifluoromethyl, phenyl, C₁₋₄-alkylphenyl, halophenyl, nitro, amino, C₂₋₄ -alkanoylamino, benzyloxyand O-phosphate, or is a heterocyclic group selected from the groupconsisting of 2-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,2-benzofuranyl, 2,3-dihydro-2-benzofuranyl, 2-benzothienyl, 2-quinolyland 2-benzopyranyl R⁵ is hydrogen or fluorine, m stands for zero, 1 or2, X is O and Y is a direct bond, --CH═CH--, --C.tbd.C-- or a group ofthe formula of

    --(Z).sub.n --A--                                          (a)

in which A is a C₁₋₈ -alkylene group which may be substituted by one ortwo phenyl groups, Z is O, S, SO or SO₂ and n stands for zero or 1, withthe proviso that R¹ is different from iodine, when R² is hydroxy orbenzoyloxy, R³ is hydrogen, R⁴ is unsubstituted phenyl, R⁵ is hydrogen,m stands for zero, X is O, and Y is a direct bond,or a tautomer thereof.2. A compound according to claim 1, wherein R¹ is fluorine, chlorine,bromine, C₁₋₄ -alkyl or halo-(C₁₋₄ -alkyl), R⁴ is a carbocyclic group asdefined in claim 1, R⁵ is hydrogen and m is zero.
 3. A compoundaccording to claim 2, wherein R¹ is C₁₋₄ -alkyl.
 4. A compound accordingto claim 3, wherein R² is hydroxy.
 5. A compound according to claim 4,wherein R³ is hydrogen.
 6. A compound according to claim 5, wherein R⁴is phenyl which may be substitued by one or more substituents selectedfrom the group consisting of halogen, C₁₋₄ -alkyl, C₁₋₄ -alkoxy,trifluoromethyl, phenyl and nitro.
 7. A compound according to claim 6,wherein m is zero.
 8. A compound according to claim 7, wherein X is O.9. A compound according to claim 8, wherein Y is a group of formula (a).10. A compound according to claim 7, wherein R¹ is ethyl, R² is hydroxy,R³ is hydrogen, R⁴ is 2-bromophenyl, 2,6-dichlorophenyl or 4-biphenylyl,m is zero, X is O and Y is a group of formula (a) as defined in claim 1in which A is --CH₂ or --CH(CH₃)-- and n is zero.
 11. A compoundaccording to claim 7, wherein R¹ is ethyl or propyl, R² is hydroxy, R³is hydrogen, R⁴ is 2-biphenylyl, 2,4-dichlorophenyl,2,4,5-trichlorophenyl, 4-chloro-2-nitrophenyl or2,4-dichloro-5-methoxyphenyl, m is zero, X is O and Y is a group offormula (a) as defined in claim 1 in which A is --CH(CH₃)-- or--CH(phenyl)--, Z is O and n is
 1. 12. A compound according to claim 1,selected from the group consistingof5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2,6-bichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,4-bichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(4-biphenylyl)acetamido]-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-phenylphenoxy)propionamido]uridine,1-[5-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil,5'-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(4-chloro-2-nitrophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,4-dichlorophenoxy)-2-phenylacetamido]-2',5'-deoxy-5-ethyluridine,5'-[2(RS)-(2,4-dichloro-5-methoxyphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridineand5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-propyluridine.13. A compound according to claim 2, selected from the group consistingof2',5'-Dideoxy-5-ethyl-5'-(2-phenylacetamido]uridine,5'-(4-Bromobenzamido)-5'-deoxythymidine,5'-deoxy-5'-(4-nitrobenzamido)thymidine, ' -benzamido-5'-deoxythymidine,5'-deoxy-5'-(2-fluorobenzamido)thymidine,5'-deoxy-5'-(2-nitrobenzamido)thymidine,5'-[2-(2-bromphenyl)acetamido]-5'-deoxythymidine,5'-deoxy-5'-[2-(4-nitrophenyl)acetamido]thymidine,5'-deoxy-5'-(2-phenylacetamido)thymidine,5'-deoxy-5'-[2-(4-trifluoromethylphenyl)acetamido]thymidine,5'-benzamido-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-(2-fluorobenzamido)uridine,5'-(2-bromobenzamido)-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-(4-nitrobenzamido)uridine,2',5'-dideoxy-5-ethyl-5'-(2-trifluoromethylbenzamido)uridine,2',5'-dideoxy-5-ethyl-5'-[2-(2,6-dimethylphenyl)acetamido]uridine,5'-[2(RS)-(2-bromophenyl)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2-chloro-3-nitrophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,6-dichlorophenyl)propionamido]-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-[2-(3,5-dimethylphenyl)acetamido]uridine,2',5'-dideoxy-5'-[2-(3,5-dimethoxyphenyl)acetamido]-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-[2-(2,3,5,6-tetramethylphenyl)acetamido]uridine,2',5'-dideoxy-5-ethyl-5'-[2-(2-methoxyphenyl)acetamido]uridine,2',5'-dideoxy-5-ethyl-5'-[2-(2-nitrophenyl)acetamido]uridine,5-bromo-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxyuridine,3'-O-butyryl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,' .5'-dideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-3'-O-(3,3-dimethylbutyryl)-5-ethyluridine,5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyl-3'-O-palmitoyluridine,3'-O-acetyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,3'-O-benzyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine,2',3',5'-trideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-5-ethyluridine,5'-[2-(2-aminophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2-acetamidophenyl)acetamido]-3'-O-acetyl-2',5'-dideoxy-5-ethyluridine,5'-[2-(2-acetamidophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridine5-(2-chloroethyl)-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2,6-dichlorophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2-bromophenyl)-N-methylpropionamido]-2',5'-dideoxy-5-ethyluridine,3'-O-acetyl-5'-[2-(2-bromophenyl)-N-methylacetamido]-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-(2-naphthalamido)uridine,2',5'-dideoxy-5-ethyl-5'-(2-phenylbenzamido)uridine,2',5'-dideoxy-5-ethyl-5'-(3-phenylpropionamido)uridine,2',5'-dideoxy-5-ethyl-5'-(4-phenylbutyramido)uridine, ' .5'-dideoxy-5'-cinnamamido-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-(3-phenyl-2-propynamido)uridine,2',5'-dideoxy-5-ethyl-5'-[3-(phenylsulfonyl)propionamido]uridine,5'-(2-bromocinnamamido)-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-[2-(2-thienyl)acetamido]uridine,2',5'-dideoxy-5-ethyl-5'-[2-(3-thienyl)acetamido]uridine,5'-(1-adamantylcarboxamido)-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-(2-pyridylcarboxamido)uridine,2',5'-dideoxy-5-ethyl-5'-(3-pyridylcarboxamido)uridine,2',5'-dideoxy-5-ethyl-5'-[2-(phenylsulfonyl)acetamido]uridine,2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine,3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine,3'-O-butyryl-2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)uridine,2',5'-dideoxy-5-ethyl-3'-O-(3,3-dimethylbutyryl)-5'-(9-fluorenylcarboxamido)uridine,2',5'-dideoxy-5-ethyl-5'-(9-fluorenylcarboxamido)-3'-O-(hexadecanoyl)uridine,2',5'-dideoxy-5-ethyl-3'-O-(9-fluorenylcarbonyl)-5'-(9-fluorenylcarboxamido)uridine,2',5'-dideoxy-5-ethyl-5'-(2-phenylbutyramido)uridine,2',5'-dideoxy-5-ethyl-5'-(3-phenylbutyramido)uridine,2',5'-dideoxy-5-ethyl-5'-(2,2-diphenylacetamido)uridine,5'-(2-cyclohexyl-2-phenylacetamido)-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-(triphenylacetamido)uridine,2',5'-dideoxy-5-ethyl-5'-(2-methyl-2-phenylpropionamido)uridine,2',5'-dideoxy-5-ethyl-5'-[2(RS)-phenylpropionamido)]uridine,5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,6-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(3,5-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2-chlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2,6-dichlorophenoxy)acetamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2,4-dichlorophenoxy)acetamido]-2',5'-dideoxy-5-ethyluridine,5'-[4-(2,6-dichlorophenoxy)butyramido]-2',5'-dideoxy-5-ethyluridine,5'-[6-(2,6-dichlorophenoxy)hexanamido]-2',5'-dideoxy-5-ethyluridine,5'-[5-(2,6-dichlorophenoxy)valeramido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2-chloro-4-nitrophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2-chloro-4-phenylphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5-bromo-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxycytidine and5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethylcytidine.
 14. Acompound according to claim 1, selected from the group consistingof5'-[2-(2,6-Dichlorophenyl)acetamido]-5'-deoxythymidine,5-bromo-5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxyuridine,5-bromo-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine,5'-benzamido-5-bromo-2',5'-dideoxyuridine, '-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-iodouridine,5'-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxy-5-iodouridine5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-iodouridine,3'-O-benzyl-5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine,5'-[2(RS)-(2,4-dichlorophenoxy)-N-methylpropionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(R)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(S)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,4-dichlorophenoxy)butyramido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(4-acetamido-2-chlorophenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2-chloro-4-methoxyphenoxy)propionamido]-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-methylbiphenylyloxy)propionamido]uridine5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-5'-deoxythymidine,5'-[2-(2,4-dichlorophenoxy)-2-methylpropionamido]-2',5'-dideoxy-5-ethyluridine,2',5'-dideoxy-5-ethyl-5'-[2(RS)-phenoxypropionamido]uridine,2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-fluorophenoxy)propionamido]uridine,2',5'-dideoxy-5-ethyl-5'-[2(RS)-(2-trifluoromethylphenoxy)propionamido]uridine,1-[5-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]thymine,'-[2(RS)-(2,4-dichlorophenylsulfinyl)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,4-dichlorophenylsulfonyl)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2-(2,6-dichlorophenylacetamido)ethyl]-2',5'-dideoxy-5-ethyluridine,5'-[2-[2(RS)-(2,4,5-trichlorophenoxy)propionamido]ethyl]-2',5'-dideoxy-5-ethyluridine,5'-[2-[2(RS)-(2,4-dichlorophenoxy)propionamido]ethyl]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,6-dichlorobenzyl)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[2(RS)-(2,4-dichlorobenzyl)propionamido]-2',5'-dideoxy-5-ethyluridine,5'-[5-chloro-2,3-dihydro-2(RS)-benzofuranylcarboxamido]-2',5'-dideoxy-5-ethyluridine,5-(6-chloro-2H-1-benzopyran-2-ylcarboxamido)-2',5'-dideoxy-5-ethyluridine,5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,3'-O-acetyl-5'-[2-(4-benzyloxy-2,6-dimethylphenyl)acetamido]-2',5'-dideoxy-5-ethyluridine,3'-O-acetyl-2',5'-dideoxy-5-ethyl-5'-[2-(4-hydroxy-2,6-dimethylphenyl)acetamido]uridine,2',5'-dideoxy-5-ethyl-5'-[2-(2,6-dimethyl-4-phosphatophenyl)acetamido]uridine,5-(2-chloroethyl)-2',5'-dideoxy-5'-[2-(2,4-dichlorophenoxy)propionamido]uridine,5'-benzamido-5-(2-chloroethyl)-2',5'-dideoxyuridine,5-(2-chloroethyl)-5'-[2-(2,4,5-trichlorophenoxy)propionamido]-2',5'-dideoxyuridine,5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-propyluridine,5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-5-propyluridine,and 5-acetyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxyuridine.15. A pharmaceutical composition comprising an effective amount of acompound of formula ##STR6## wherein R¹ is halogen, C₁₋₄ -alkyl,halo-(C₁₋₄ -alkyl) or C₂₋₄ -alkanoyl,R² is hydrogen, hydroxy, C₁₋₄-alkoxy-C₁₋₄ -alkylthio, phenyl-(C₁₋₄ -alkoxy) or C₂₋₄ -alkanoyloxy, R³is hydrogen or C₁₋₄ -alkyl, R⁴ is a carbocyclic group selected from thegroup consisting of 2-biphenylyl, 4-biphenylyl, 3-chloro-4-biphenylyl,1-naphthyl, 2-naphthyl, cyclopentyl, cyclohexyl, adamantyl, indanyl,fluorenyl and phenyl which may be substituted by one or moresubstituents selected from the group consisting of halogen, hydroxy,C₁₋₄ -alkyl, C₁₋₄ -alkoxy, trifluoromethyl, phenyl, C₁₋₄ -alkylphenyl,halophenyl, nitro, amino, C₂₋₄ -alkanoylamino, benzyloxy andO-phosphate, or is a heterocyclic group selected from the groupconsisting of 2-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,2-benzofuranyl, 2,3-dihydro-2-benzofuranyl, 2-benzothienyl, 2-quinolyland 2-benzopyranyl R⁵ is hydrogen or fluorine, m stands for zero, 1 or2, X is O and Y is a direct bond, --CH═CH--, --C.tbd.C-- or a group ofthe formula of

    --(Z).sub.n --A--                                          (a)

in which A is a C₁₋₈ -alkylene group which may be substituted by one ortwo phenyl groups, Z is O, S, SO or SO₂ and n stands for zero or 1, withthe proviso that R¹ is different from iodine, when R² is hydroxy orbenzyloxy, R³ is hydrogen, R⁴ is unsubstituted phenyl, R⁵ is hydrogen, mis zero, X is O, and Y is a direct bond, or a tautomer thereof, and aninert carrier.
 16. A pharmaceutical composition according to claim 15,R¹ is fluorine, chlorine, bromine, C₁₋₄ -alkyl or halo-(C₁₋₄ -alkyl), R⁴is a carbocyclic group as defined in claim 1, R⁵ is hydrogen and m iszero.
 17. A pharmaceutical composition according to claim 16, wherein R¹is C₁₋₄ -alkyl.
 18. A pharmaceutical according to claim 17, wherein R²is hydroxy.
 19. A pharmaceutical composition according to claim 18,wherein R³ is hydrogen.
 20. A pharmaceutical composition according toclaim 19, wherein R⁴ is phenyl which may be substituted by one or moresubstituents selected from the group consisting of halogen, C₁₋₄ -alkyl,C₁₋₄ -alkoxy, trifluoromethyl, phenyl and nitro.
 21. A pharmaceuticalcomposition according to claim 20, wherein m is zero.
 22. Apharmaceutical composition according to claim 21, wherein X is O.
 23. Apharmaceutical composition according to claim 22, wherein Y is a groupof formula (a) as defined in claim
 1. 24. A pharmaceutical compositionaccording to claim 21, wherein R¹ is ethyl, R² is hydroxy, R³ ishydrogen, R⁴ is 2-bromophenyl, 2,6-dichlorophenyl or 4-biphenylyl, m iszero, X is O and Y is a group of formula (a) as defined in claim 1 inwhich A is --CH₂ or --CH(CH₃)-- and n is zero.
 25. A pharmaceuticalcomposition according to claim 21, wherein R¹ is ethyl or propyl, R² ishydroxy, R³ is hydrogen, R⁴ is 2-biphenylyl, 2,4-dichlorophenyl,2,4,5-trichlorophenyl, 4-chloro-2-nitrophenyl or2,4-dichloro-5-methoxyphenyl, m stands for zero, X is O and Y is a groupof formula (a) in which A is --CH(CH₃)-- or --CH(phenyl)--, Z is O and nis 1.